Antiretroviral tetrahydroimidazo[1,4]benzodiazepin-2(thi) ones

ABSTRACT

The compounds are of the class 1,4-benzodiazepines of the formula:                    
     An illustrative compound is ( S )-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine. The compounds are useful as intermediates in the preparation of tetrahydroimidazo[1,4]benzodiazepin-2-(thi)ones.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division of our application Ser. No. 08/132,030, filed on Oct.5, 1993, now U.S. Pat. No. 5,371,079, which in turn was a division ofour application Ser. No 08/042,858, filed Apr. 5, 1993, now U.S. Pat.No. 5,270,464, which in turn was a continuation of application Ser. No.07/671,238, filed Mar. 19, 1991, now abandoned, which was acontinuation-in-part of our application Ser. No 07/583,533 filed Sep.17, 1990 now abandoned which in turn is a continuation-in-part of Ser.No. 07/323,585, filed Mar. 14, 1989, now abandoned; and of Ser. No.07/476,926 filed Feb. 8, 1990, now abandoned which is acontinuation-in-part of Ser. No. 07/406,626 filed Sep. 13, 1989, nowabandoned; and of Ser. No. 07/549,349, filed Jul. 6, 1990 now abandoned;and of Ser. No. 07/549,777, filed Jul. 9, 1990 now abandoned which is acontinuation-in-part of Ser. No. 07/406,625 filed Sep. 13, 1989, nowabandoned.

BACKGROUND OF THE INVENTION

In the Eur. J. Med. Chem. 1978, 13 53-59, there are described threetetrahydroimidazo[4,5,1-jk][1,4]benzodiazepines. The compounds of thepresent invention differ there-from by the fact that the imidazo-moietyis substituted with an oxo or thio group and that said compounds showantiviral activity.

DESCRIPTION OF THE INVENTION

The present invention is concerned withtetrahydroimidazo[1,4]benzodiazepin-2-(thi)ones having the formula:

the pharmaceutically acceptable acid addition salts and thestereochernically isomeric forms thereof, wherein:

X is O or S;

R¹ is C₁₋₆alkyl optionally substituted with aryl; C₃₋₆alkynyl;C₃₋₆cycloalkyl; or a radical of formula:

Alk is C-₁₋₆alkanediyl;

R⁸ and R⁹ each independently are hydrogen, halo, C₃₋₆cycloalkyl,trifluoromethyl, 2,2,2-trifluoroethyl, C₁₋₄alkyl optionally substitutedwith

C₁₋₄alkyloxy;

R¹⁰ is hydrogen, halo or C₁₋₄alkyl;

each R¹¹ independently is hydrogen or C₁₋₄alkyl; or both R¹¹ takentogether may form a C₁₋₆alkanediyl radical;

R¹² is hydrogen, halo or C₁₋₄alkyl;

n is 2, 3, 4, 5 or 6;

each R¹³ independently is hydrogen or C₁₋₄alkyl; or both R¹³ takentogether may form a C₁₋₆alkanediyl radical;

R¹⁴ is hydrogen or C₂₋₆alkenyl;

R² is hydrogen or methyl;

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ each independently are hydrogen, C₁₋₆alkyl, halo, cyano,nitro, trifluoromethyl, hydroxy, C₁₋₆alkyloxy, amino, mono-ordi(C₁₋₆alkyl)amino or C₁₋₆alkylcarbonylamino;

R⁶ is hydrogen or methyl;

R⁷ is hydrogen or methyl;

each aryl is phenyl optionally substituted with from 1 to 3 substituentsindependently selected from C₁₋₆alkyl, halo, hydroxy, C₁₋₆alkyloxy,amino, nitro and trifluoromethyl.

The compounds of formula (I) may also exist in their tautomeric form.Said tautomeric form, indicated below, is intended to be included withinthe scope of the present invention.

In the foregoing definitions the term halo is generic to fluoro, chloro,bromo and iodo; C₁₋₄alkyl defines straight and branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as, forexample, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl and the like; C₁₋₆alkyl definesC₁₋₄alkyl radicals as defined hereinabove and the higher homologsthereof having from 5 to 6 carbon atoms; C₁₋₆alkanediyl defines bivalentstraight or branched chain hydrocarbon radicals containing 1 to 6 carbonatoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl,1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomersthereof; C₂₋₆alkenyl defines straight and branched hydrocarbon radicalscontaining one double bond and having from 2 to 6 carbon atoms such as,for example, ethenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, pentenyl, hexenyl and the like; C₃₋₆alkynyl definesstraight and branched chain hydrocarbon radicals containing a triplebond and having from 3 to 6 carbon atoms such as, for example,2-propynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl and the like;C₃₋₆cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

Each R¹¹, R¹³ and R¹⁴ in the radicals of formula (a-2) and (a-3), whenbeing as defined hereinbefore but other than hydrogen, is meant toreplace a hydrogen atom of the —(CH₂)_(n)— or the —CH— moiety in saidradicals.

Depending on the nature of the various substituents, the compounds offormula (I) may have several asymmetric carbon atoms. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereo-chemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure. The absolute configuration of each chiral centermay be indicated by the stereochemical descriptors R and S, this R and Snotation corresponding to the rules described in Pure Appl. Chem. 1976,45, 11-30. Stereochemically isomeric forms of the compounds of formula(I) are obviously intended to be embraced within the scope of theinvention.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxic acidaddition salt forms by treatment with appropriate acids, such as, forexample, inorganic acids, e.g. hydrochloric, hydrobromic and the likeacids, sulfuic acid, nitric acid, phosphoric acid and the like; ororganic acids, such as, for example, acetic, propanoic, hydroxyacetic,2-hydroxy-propanoic, 2-oxopropanoic, ethanedioic, propanedioic,butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4methyl-benzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alki into the free base form. Theterm pharmaceutically acceptable acid addition salts also comprises thesolvates which the compounds of formula (I) may form and said solvatesare intended to be included within the scope of the present invention.Examples of such solvates are e.g. the hydrates, alcoholates and thelike.

A first interesting group of compounds of formula (I) are those whereinR¹ is C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl or C₁₋₆alkylsubstituted with C₃₋₆cycloalkyl; and/or R⁴ and R⁵ each independently arehydrogen, C₁₋₆alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy,C₁₋₆alkyloxy, amino or mono- or di(C₁₋₆alkyl)amino; and/or R⁶ and R⁷ arehydrogen; and R², R³, X and aryl are as defined under formula (I).

A second interesting group of compounds of formula (I) are those whereinR¹ is C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl or C₁₋₆alkylsubstituted with C₃₋₆cycloalkyl; and/or R⁴ and R⁵ each independently arehydrogen, C₁₋₆alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy,C₁₋₆alkyloxy, amino or mono- or di(C₁₋₆alkyl)amino; and/or R⁶ is methyl,R⁷ is hydrogen; and R², R³, X and aryl are as defined under formula (I).

More interesting compounds are those compounds of formula (I) or thosecompounds comprised within the abovementioned interesting groups,wherein R¹ is C₁₋₆alkyl, C₃₋ ₆alkynyl or a radical of formula (a-1),(a-2) or (a-3); and/or R⁴ and R⁵ each independently are hydrogen,C₁₋₆alkyl, halo, cyano, nitro, amino, trifluoromethyl, hydroxy orC₁₋₆alkyloxy.

A first particular subgroup comprises those more interesting compoundswherein R² and R³ each independently are hydrogen or methyl; and/or X isO.

A second particular subgroup comprises those more interesting compoundswherein R² and R³ each independently are hydrogen or methyl; and/or X isS.

More particular compounds are those compounds comprised within theabove-mentioned particular subgroups wherein R¹ is C₃₋₆alkyl or aradical of formula (a-1) wherein R⁸ and R⁹ each independently areC₃₋₆cycloalkyl, trifluoromethyl or C₁₋₄alkyl; or a radical of formula(a-3) wherein n is 2 or 3; and/or R⁵ and R⁷ are hydrogen.

Preferred compounds are those more particular compounds wherein R⁸ andR⁹ each independently are C₁₋₃alkyl; and/or each R¹³ and R¹⁴ arehydrogen; and/or R⁶ is hydrogen.

More preferred compounds are those preferred compounds wherein R¹ ispropyl; 3,3-dimethylbutyl; methylcyclopropyl optionally substituted withone or two methyl groups and/or one 2-methylpropenyl group;methylcyclobutyl; 2-propenyl; 2-butenyl; 2-methyl-2-butenyl;3-methyl-2-butenyl, 2,3 dinethyl-2-butenyl or 3-ethyl-2-pentenyl; and/orR⁴ is hydrogen, methyl, chloro or bromo.

The most preferred compounds are

(+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;

(+)-(S)4,5,6,7-tetrahydro-5,8-dimethyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;

(+)-(S)-8-bromo4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;

(+)-(S)-8-chloro-6-(3-ethyl-2-pentenyl)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thioneand

(+)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione.

In the following paragraphs, there are described different ways ofpreparing compounds of formula (I).

The compounds of formula (I) can generally be prepared by condensing a9-amino-2,3,4,5-tetaahydro-1H-1,4-benzodiazepine of formula (II) with areagent of formula (III), wherein L is an appropriate leaving group.

Appropriate agents of formula (III) are for example urea,di(C₁₋₆alkyl)carbonate, carbonoic dichloride, trichloromethylchloroformate, 1,1′-carbonylbis[1H-imidazole], alkali metal, alkalineearth metal or ammonium isocyanates, phenyl isocyanate, benzoylisocyanate, thiourea, carbonothioic dichloride, carbon disulfide,1,1′-carbonothioyl-bis[1H-imidazole], xanthogenates, alkali metal,alkaline earth metal or ammonium isothiocyanates, phenyl isothiocyanate,benzoyl isothiocyanate, 1,3-dithiolane-2-thione and the like. Saidcondensation reaction may conveniently be conducted by stiring andoptionally heating the reactants in a reaction-inert solvent, such as,for example, an aromatic hydrocarbon, e.g. benzene, methylbenzene,dimethylbenzene and the like; a halogenated hydrocarbon, e.g.trichloromethane, tetrachloromethane, chlorobenzene and the like; anether, e.g. tetrahydrofuran, 1,4-dioxane, 1,1′-oxybisbutane,1,1′-oxybis-(2-methoxyethane), 1,2-bis(2-methoxyethoxy)ethane and thelike; a dipolar aprotic solvent, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone,pyridine, methylpyridine, dimethylpyridine, tetrahydrothiophene1,1-dioxide and the like; or a mixture of such solvents. In someinstances however, it may be preferable to heat the reactants without asolvent. Further it may be appropriate to add to the reaction mixture abase such as, for example, a tertiary amine, e.g. N,N-diethylethanamine,N-ethyl-N-(1-methylethyl)-2-propanamine, 4-methylmorpholine and the likeamines. When said reagent of formula (III) is carbon disulfide, thereaction can also be conducted conveniently in an alkanol such as, forexample, methanol, ethanol, propanol and the like, in the presence of abase such as sodium or potassium hydroxide and the like or in carbondisulfide as solvent and in the presence of a suitable base such as, forexample, an alkyl magnesium halide, e.g. ethyl magnesium bromide, analkyl lithium, e.g. butyllithium, an amine, e.g., N,N-diethylethanamine,a carbodiimide, e.g. N,N-dicyclohexylcarbodiimide and the like reagents.Or, alternatively the latter reaction may also be conducted in basicsolvent such as, for example, pyridine and the like, in the presence ofa phosphite such as, for example, diphenylphosphite.

The compounds of formula (I) can also be prepared by reacting a4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine derivative offormula (IV) with a reagent of formula M₂X (V), wherein X is as definedhereinabove.

In formula (IV), L⁰ is a reactive leaving group such as, for example,halo, e.g. chloro, bromo and the like groups. Appropriate reagents offormula M₂X (V) are for example, water, urea, thiourea, alkali metalthiosulfates, e.g. sodium thiosulfate and the like reagents. Saidreaction can conveniently be conducted by stirring and optionallyheating the reactants in a reaction-inert solvent such as, for example,water, an alkanol, e.g., methanol, ethanol, 1-propanol, 2-propanol,butanol, 1,2-ethanediol and the like; or an aromatic hydrocarbon, e.g.benzene, methylbenzene, dimethylbenzene and the like; a halogenatedhydrocarbon, e.g. trichloromethane, tetrachloromethane, chlorobenzeneand the like; an ether, e.g. tetrahydrofuran, 1,4-dioxane,1,1′-oxybisbutane, 1,1′-oxybis(2-methoxyethane),1,2-bis(2-methoxyethoxy)ethane and the like; a dipolar aprotic solvent,e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide,1-methyl-2-pyrrolidinone, pyridine, methylpyridine, dimethylpyridine,tetrahydrothiophene, 1,1-dioxide and the like; or a mixture of suchsolvents. In some cases it may be appropriate to conduct said reactionin an excess of the reagent of formula (V), optionally in the presenceof a reaction-inert solvent as defined above. In particular, thereaction may be conducted at an elevated temperature, more particularlythe reflux temperature of the reaction mixture. Further, it may beappropriate to add to the reaction mixture a base such as, for example,an amine, e.g. N,N-diethylethanamine,N-ethyl-N-(1-methylethyl)-2-propanamine, 4-methylmorpholine and the likeamines.

The compounds of formula (I) can also be obtained by N-alkylating anintermediate mediate of formula (VI) with a reagent of formula R¹—W(VII) wherein W represents an appropriate reactive leaving group suchas, for example, halo, e.g. chloro, bromo or iodo; or a sulfonyloxygroup, e.g. benzenesulfonyloxy, 4-methylbenzenesulfonyloxy,methanesulfonyloxy and the like.

Said N-alkylation reaction may conveniently be conducted in areaction-inert solvent such as, for example, an aromatic hydrocarbon,e.g., benzene, methylbenzene, dimethylbenzene and the like; a loweralkanol, e.g., methanol, ethanol, 1-butanol and the like; a ketone,e.g., 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g.,1,4-dioxane, 1,1′-oxybisethane, tetrahydrofuran and the like; a dipolaraprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide,nitrobenzene, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, and thelike, or a mixture of such solvents. The addition of an appropriate basesuch as, for example, an alkali metal carbonate or hydrogen carbonate,e.g. sodium carbonate, sodium hydrogen carbonate; sodium hydride or anorganic base such as, for example, N,N-diethylethanamine orN-(1-methylethyl)-2-propanamine and the like may be utilized to pick upthe acid which is liberated during the course of the reaction. In somecircumstances the addition of an iodide salt, preferably an alkali metaliodide, e.g. potassium iodide, is appropriate. Somewhat elevatedtemperatures and stirring may enhance the rate of the reaction.

The compounds of formula (I) wherein R¹ is C-₁₋₆alkyl optionallysubstituted with aryl; C₃₋₆cycloalkyl or a radical of formula (a-3) andthe carbon atom of said R¹ radical adjacent to the nitrogen atom bearingsaid R¹ contains at least one hydrogen atom, said radicals beingrepresented by R^(1−a), and said compounds by formula (I-a), may also beprepared by the reductive N-alkylation of an intermediate of formula(VI) with a ketone or aldehyde of formula R^(1−b)═O (VIII). In formula(VIII), R^(1−b) represents a geminal bivalent radical derived fromR^(1−a)—H wherein two geminal hydrogen atoms are replaced by ═O.

Said reductive N-alkylation reaction may conveniently be carried out bycatalytically hydrogenating the reactants in a suitable reaction-inertorganic solvent according to art-known catalytic hydrogenationprocedures. The reaction mixture may be stirred and/or heated in orderto enhance the reaction rate. Suitable solvents are, for example, water;C₁₋₆alkanols, e.g. methanol, ethanol, 2-propanol and the like; ethers,e.g. 1,4-dioxane and the like; halogenated hydrocarbons, e.g.trichloromethane and the like; dipolar aprotic solvents, e.g.N,N-dimethylformamide, dimethyl sulfoxide and the like; esters, e.g.ethyl acetate and the like; or a mixture of such solvents. The termart-known catalytic hydrogenation procedures means that the reaction iscarried out under a hydrogen atmosphere and in the presence of anappropriate catalyst such as, for example, palladium-on-charcoal,platinum-on-charcoal and the like. In order to prevent the undesiredfurther hydrogenation of certain functional groups in the reactants andthe reaction products it may be advantageous to add an appropriatecatalyst-poison to the reaction mixture, e.g., thiophene and the like.Alternatively, said reductive N-alkylation may also be performedfollowing art-known reduction procedures by treating a stirred and, ifdesired, heated mixture of the reactants with a reducing agent such as,for example, sodium borohydride, sodium cyanoborohydride, formic acid ora salt thereof, in particular the ammonium salt thereof.

The compounds of formula (I) wherein X is S, said compounds beingrepresented by formula (I-b-2), can be prepared by thionation of thecompounds of formula (I) wherein X is O, said compounds represented byformula (I-b-1), with phosphorus pentasulfide in an appropriatereaction-inert solvent. Such solvents are for example, aromatichydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene, dipolaraprotic solvents, e.g. hexamethylphosphoric triamide (HMPA) and the likesolvents.

Based on the currently available test data, it appears that thecompounds6allyl-4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-oneand(R)-4,5,6,7-tetrahydro-5-methyl-6-(2-propenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-onehave a disfavorable therapeutic index. However, these compounds offormula (I-b-1) are useful as intermediates for preparing the compoundsof formula (I-b-2). This also applies for the compounds of formula(1-b-1) wherein R¹ is phenylmethyl or phenylethyl, R² is hydrogen ormethyl and R³, R⁴, R⁵, R⁶ and R⁷ are hydrogen, which also have adisfavorable therapeutic index according to the available test data.

The compounds of formula (I-b-2) may also be obtained by direct thiationof a tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine of formula (IX) withelemental sulfur at an elevated temperature.

Said reaction may conveniently be conducted without a solvent at atemperature above 200° C., more particularly a temperature in the rangeof 230 to 250° C.

The compounds of formula (I-b-2) may alternatively be prepared by thecombined reduction-thiocarbonylation of a 9-nitrobenzodiazepine offormula (X) in the presence of an alkali metal sulfide or hydrogensulfide, and carbon disulfide.

Said reduction-thiocarbonylation reaction may conveniently be conductedby stirring the reactants in a reaction-inert solvent, optionally at anelevated temperature.

The compounds of formula (I) can also be prepared by deprotecting theintermediates of formula (VI-P) followed by N-alkylation with a reagentof formula R¹—W (VII) as described for the preparation of (I) from (VI)and (VI).

P represents a suitable protective group like a C₁₋₄alkyloxycarbonyl,e.g., t.butyloxycarbonyl, benzyloxycarbonyl and the like, which can beremoved by hydrolysis in an acid or alkaline medium.

In all of the foregoing and in the following preparations, the reactionproducts may be isolated from the reaction mixture and, if necessary,further purified according to methodologies generally known in the art.

A number of intermediates and starting materials in the foregoingpreparations are known compounds which may be prepared according toart-known methodologies of preparing said or similar compounds and someintermediates are new. A number of such preparation methods will bedescribed hereinafter in more detail.

The intermediates of formula (II) can generally be prepared from a9-aminobenzodiazepine of formula (II-a) following N-alkylation reactionprocedures such as described hereinabove for the preparation of thecompounds of formula (I) and (I-a) from an intermediate of formula (VI)with an alkylating reagent (VII) or with an aldehyde or ketone offormula (VIII).

In order to simplify the following reaction schemes, the N-alkylatedintermediates wherein R¹ is as defined under formula (I) and theN-unsubstituted intermediates (wherein R¹ is replaced by hydrogen) willbe represented hereinafter by formulae wherein the N atom at the 4position is substituted with R^(1H), said R^(1H) defining R¹ andhydrogen. In intermediates (II-H), (XI) and (XII) of scheme 1hereinbelow, R^(1H) also defines a radical of formula:

The latter amide intermediates can conveniently be prepared followingart-known N-acylation procedures from corresponding intermediateswherein R^(1H) is hydrogen and can be reduced to the correspondingN-alkylated intermediates with complex metal hydrides or hydrides asdescribed under reaction step A of scheme 1. In all of the followingreaction schemes, the intermediates wherein R^(1H) is hydrogen can alsobe converted into intermediates wherein R^(1H) is R¹ following the abovedescribed N-alkylation procedures with an alkylating reagent of formulaR¹—W (VII) or with an aldehyde or ketone of formula R^(1−b)═O (VIII).

The intermediates of formula (II-H), said intermediates representing theintermediates of formula (II) and (II-a) can generally be preparedfollowing the reaction steps shown in the reaction scheme 1 below.

The 9-aminobenzodiazepine (II-H) in the above reaction scheme mayconveniently be prepared by reduction of the corresponding nitrobenzenederivative (XI) following art-known nitro-to-amine reduction procedures(reaction step A). Said reduction may conveniently be conducted bytreatment of said nitrobenzenes with a reducing agent such as, forexample, a complex metal hydride, e.g. lithium aluminum hydride; ahydride, e.g. diborane, aluminum hydride and the like, in areaction-inert solvent such as, for example, 1,1′-oxybisethane,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like,optionally in the presence of a cosolvent such as an aromatichydrocarbon, e.g. benzene, methylbenzene and the like, and, if desired,at an elevated temperature. Alternatively, said reduction may also beaccomplished by treatment of said nitrobenzene derivative with sodiumdithionite, sodium sulfide, sodium hydrogen sulfide, titanium(III)chloride and the like reducing agents in a suitable solvent, inparticular water. Said nitro-to-amine reduction can also be conductedfollowing art-known catalytic hydrogenation procedures. For example,said reduction may be carried out by stirring the reactants under ahydrogen atmosphere and in the presence of an appropriate catalyst suchas, for example, palladium-on-charcoal, platinum-on-charcoal,Raney-nickel and the like catalysts. Suitable solvents are, for example,water, alkanols, e.g. methanol, ethanol and the like, esters, e.g. ethylacetate and the like. In order to enhance the rate of said reductionreaction it may be advantageous to elevate the temperature and/or thepressure of the reaction mixture. Undesired further hydrogenation ofcertain functional groups in the reactants and the reaction products maybe prevented by the addition of a catalyst poison such as, for example,thiophene and the like, to the reaction mixture.

The 9-nitrobenzodiazepine (XI) in the above reaction scheme 1 can beprepared from the benzodiazepine (XII) following art-known nitrationprocedures (reaction step B). For example, the starting material may benitrated by treatment with concentrated or fuming nitric acid in thepresence of concentrated sulfuric acid and optionally in the presence ofa cosolvent such as, for example, a halogenated hydro-carbon, e.g.dichloromethane, trichloromethane, tetrachloromethane and the likesolvents. Alternatively, said nitration may in some instances also beaccomplished by adding the nitrate salt of the starting material toconcentrated sulfuric acid.

The intermediates of formula (II-H) wherein R⁶ and R⁷ are hydrogen, saidintermediates being represented by (II-H-1) may be obtained followingthe reaction steps shown in reaction scheme 2 below. Reaction stepsdesignated A and B are intended to refer back to the analogous reactionsteps described in the previous reaction scheme.

The benzodiazepine derivatives (XIII), (XIV) and (XV) may be obtainedfrom the corresponding aniline derivatives (XVI), (XVII) and (XVII)(Reaction step C) by cyclization. Said cyclization reaction may beconducted by stirring, and, if desired, heating the starting material.Suitable solvents are, for example, aromatic hydrocarbons, e.g. benzene,methylbenzene, dimethylbenzene and the like, halogenated hydrocarbons,e.g. trichloromethane, tetrachloromethane, chlorobenzene and the like,ethers, e.g. tetrahydrofuran, 1,4-dioxane and the like, dipolar aproticsolvents e.g. N,N-dimethylformamide, N,N-dimethylacetamide,acetonitrile, dimethylsulfoxide, pyridine and the like. Bases which maybe employed in said cyclization reaction are, for example, alkali metalor alkaline earth metal carbonates, hydrogen carbonates, hydroxides,oxides, amides, hydrides and the like. In some instances the addition tothe reaction mixture of a iodide salt, preferably an alkali metaliodide, e.g. potassium iodide, may be advantageous.

The aniline derivatives (XVI), (XVII) and (XVIII), wherein W is areactive leaving group as defined hereinbefore, may be prepared from thecorresponding alkanols by treatment with a halogenating reagent such as,for example, thionyl chloride, phosphoryl chloride, phosphoroustrichloride and the like; or by treatment with a sulfonylating reagent,e.g. methanesulfonyl chloride, 4-methylbenzenesulfonyl chloride and thelike (Reaction step D).

Said alkanols (XIX), (XX) and (XXI) may be prepared by N-acylating anethanolamine of formula R^(1H)NH—CH(R²)—CH(R³)—OH (XXVII) with anappropriately substituted 2-aminobenzoic acid derivative of formula(XXII), (XXIII) or (XXIV) wherein L¹ represents hydroxy or a leavinggroup such as, for example, halo, e.g. chloro or bromo;alkylcarbonyloxy, e.g. acetyl; alkyloxy, e.g. methoxy, ethoxy and thelike; or imidazolyl and the like leaving groups. Said N-acylationreaction (reaction step E) may be carried out by stirring the reactantsin a reaction-inert solvent, optionally at an elevated temperature. Inthose instances where L¹ represents hydroxy, said N-acylation reactionmay also be carried out by treating the reactants with reagents capableof forming amides such as, for example, N,N-dicyclohexylcarbodiimide(DCC) optionally in the presence of a catalyst such ashydroxybenzotriazole (HOBT) or 4-dimethylaminopyridine (DMAP);2-chloro-1-methylpyridinium iodide, 1,1′-carbonylbis[1H-imidazole],1,1′-sulfonylbis[1H-imidazole] and the like reagents. Suitable solventsare halogenated hydrocarbons, e.g. dichloromethane, trichloromethane andthe like, ethers, e.g. tetrahydrofuran, 1,4-dioxane and the like,dipolar aprotic solvents, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, pyridine and the like; or mixtures of suchsolvents.

The intermediates of formula (II-H-1) can be prepared from a 9-amino- ora 9-nitrobenzodiazepin-5-one of formula (XII) or (XIV) by reduction witha complex metal hydride e.g. lithium aluminum hydride and the like in asuitable reaction-inert solvent such as, for example,1,2-dimethoxyethane, 1,1′-oxybis(2-methoxyethane),2,5,8,11-tetraoxadodecane, methoxybenzene and the like solvents(Reaction steps F and G). In order to enhance the rate of said reductionreaction it may be advantageous to employ an excess of the reducingreagent and to conduct said reaction at an enhanced temperature of thereaction mixture, in particular the reflux temperature of the reactionmixture.

The intermediates of formula (XIV) can alternatively be obtained from anappropriately substituted nitrobenzene (XXV) by a condensation reaction(reaction step H) with a diamino reagent R^(1H)NH—CH(R²)—CH(R³)—NH₂ offormula (XXVI) in a suitable reaction-inert solvent such as, forexample, an alkanol, e.g. methanol, ethanol, 2-propanol, 1-butanol andthe like; an aromatic hydrocarbon, e.g. benzene, methylbenzene,dimethylbenzene and the like; a halogenated hydrocarbon, e.g.trichloromethane, tetrachloromethane and the like; an ether, e.g.tetrahydofuran, 1,4-dioxane, 1,1′-oxybisbutane,1,1′-oxybis(2-methoxyethane) and the like; a ketone, e.g. 2-propanone,4-methyl-2-pentanone and the like; a dipolar aprotic solvent, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and thelike; or a mixture of such solvents. It may be appropriate to add a basesuch as an alkali metal or an alkaline earth metal carbonate, e.g.sodium carbonate, sodium hydrogen carbonate and the like, to thereaction mixture. Said condensation reaction can conveniently beconducted at an elevated temperature, in particular at the refluxtemperature of the reaction mixture.

The intermediates of formula (II-H-1) wherein R³ is hydrogen, saidintermediates being represented by formula:

can also be prepared from a benzodiazepinedione of formula

following the reduction procedures as described hereinabove forconverting intermediate (XIII) into intermediate (II-H-1) (reaction stepF). The preparation of the intermediates of formula (XXVIII) maygenerally be conducted following the reaction pathways described inscheme 3 hereinbelow.

In all of the following reaction schemes, those intermediates wherein R³is hydrogen, are designated by appending the suffix-α to their numericalreference, and the intermediates wherein R⁶ and R⁷ are hydrogen, aredesignated by appending the suffix-1- to their numerical reference.

In a number of the intermediates shown in scheme 3, for example in(XXVIII), (XXIX), (XXX), (XXXI), (XXXII) and (XXIII) it is furtherpossible to selectively reduce functional groups such as the nitrogroup, the ester group and/or the aliphatic amide group, in the presenceof the aromatic amide group (reaction step I). Said selective reductionmay be carried out by treatment of the appropriate starting materialwith a complex metal hydride such as, for example, lithium aluminumhydride in a reaction-inert solvent such as, for example,tetrahydrofuran, 1,4-dioxane and the like. Alternatively, said selectivereduction may also be performed by treatment of the appropriate startingmaterial with sodium bis(2-methoxyethoxy) aluminum hydride, or withsodium borohydride in the presence of a suitable metal salt such as, forexample, titanium(IV)chloride, calcium chloride, cerium(III) chloride,aluminum chloride, zirconium(IV)chloride and the like metal salts, in areaction-inert solvent, in particular an ether.

The benzodiazepinediones (XXVIII) and (XXX) in scheme 3 can be obtainedby cyclizing (reaction step J) the corresponding acyclic intermediatesof formula (XXXI) and (XXXIII) wherein R represents a group such asC₁₋₆alkyl or aryl,

a) by heating without a solvent under an inert atmosphere, optionallyunder reduced pressure;

b) by treating with a bifunctional catalyst such as, for example, aceticacid, 2-hydroxypyridine, pyrarole, 1,2,4-triazole and the like, in areaction-inert solvent such as, for example, an aromatic hydrocarbon,e.g. methylbenzene, dimethylbenzene and the like, optionally at anelevated temperature; or

c) by hydrolyzing the ester and subsequently treating the correspondingcarboxylic acid (R═H) with an appropriate acid, such as, for example, ahydrohalic acid, e.g. hydrochloric acid; sulfuric acid, phosphoric acidand the like acids; or with a halogenating reagent such as, for example,thionyl chloride and the like.

Said intermediates in tum, can be prepared from an appropriatelyprotected amino acid of formula R^(1H)—NH—CH(R²)—COOR (XL) wherein R isC-₁₋₆alkyl or aryl, by a N-acylation reaction (reaction step K) with anappropriately substituted isatoic anhydride derivative or an appropriate2-aminobenzoic acid derivative, by stirring the reactants at refluxtemperature in a reaction-inert solvent such as, for example,trichloromethane, pyridine and the like solvents.

The intermediates of formula (II-H), wherein R³ is hydrogen, saidintermediates being repesented by (II-H-α) may be prepared frombenzodiazepin-2-one derivatives following the procedures described inscheme 4.

Reaction steps A, B, I and J are intended to refer back to the analogousreaction steps described hereinbefore.

The intermediates of formula (XLIV), (XLV) and (XLVI) can be preparedfrom an appropriately protected amino acid of formulaR^(1H)NH—CH(R²)—COOR (XL) wherein R is C₁₋₆alkyl or aryl, by aN-alkylation reaction (reaction step L) with an intermediate of formula(XLVII), (XLVIII) and (IL) in a reaction inert solvent.

The intermediates of formula (II-H) wherein R⁶ and R⁷ are hydrogen andR³ is C₁₋₆alkyl, said radical being represented by R^(3-a) and saidintermediates by formula:

can be prepared by the reduction of an amine (XHI-b) or an imine (L),following the reduction procedures as described hereinabove for thepreparation of (II-H-1) from (XIII) or (XIV).

The imine (L) can be prepared by reducing a nitro derivative (LI) in thepresence of hydrogen and a suitable metal catalyst such as, for example,palladium-on-charoal, platinum oxide and the like catalysts. The ketoneof formula (LI) in turn can be prepared from a 2-amino-3-nitrobenzoicacid or a functional derivative thereof (XXIII) and an α-aminoketone(LII) following art-known N-acylation procedures.

The intermediates of formula (IV) can generally be prepared from thecompounds of formnula (I-b-1) by reacting with a halogenating reagentsuch as, for example, phosphoryl chloride, phosphorous trichloride,phosphorous tribromide, thionyl chloride, and the like reagents,optionally at an elevated temperature, in particular the refluxtemperature of the reaction mixture, and optionally in the presence of abase such as, for example, sodium carbonate, sodium hydrogen carbonate,potassium carbonate and the like. The reaction can be conducted in anexcess of the halogenating reagent as solvent and optionally areaction-inert solvent such as an aromatic hydrocarbon or an ether maybe used as well. Or alternatively, the compounds of formula (I-b-1) canbe reacted with an acid anhydride, e.g. trifluoroacetic anhydride toform an O-acylated intermediate which can be further converted with ahydrogen halide, such as hydrogen chloride, into intermediates offormula (IV). The reaction can be carried out in a reaction-inertsolvent like an aromatic hydrocarbon or an ether in the presence of abase, such as, for example, a pyridine, e.g. a picoline, 2,6-lutidineand the like.

The intermediates of formula (VI) wherein R², R³, R⁴, R⁵, R⁶, R⁷ and Xare as defined under formula (I) are novel and can be prepared fromintermediates of formula (II-a) following the condensation reaction witha reagent of formula L—C(═X)—L (III) as described hereinbefore for thepreparation of the compounds of formula (I) from the intermediates offormula (II).

The intermediates of formula (VI) can also be obtained from a benzylatedcompound of formula (I-c) following art-known hydrogenolysis procedures.

Said debenzylation reaction can be accomplished by stirring a compoundof formula (I-c) in an appropriate reaction-inert solvent in thepresence of a suitable metal catalyst and under a hydrogen atmosphere.Appropriate solvents are, for example, alkanols, e.g. methanol, ethanoland the like; carboxylic esters, e.g. ethyl acetate; carboxylic acids,e.g. acetic acid, propanoic acid and the like. As examples of suitablemetal catalysts there may be mentioned palladium-on-charcoal,platinum-on-charcoal and the like catalysts. In order to prevent thefurther hydrogenation of the starting material and/or the reactionproduct it may be appropriate to add a catalyst-poison to the reactionmixture such as, for example thiophene.

The intermediates of formula (VI) wherein R⁶ and/or R⁷ are methyl, saidintermediates being represented by formula (VI-a) and (VI-b) can beprepared from 9-aminobenzodiazepin-5-ones of formula (XIII-a) as shownin the next reaction scheme.

The benzodiazepin-7-ones of formula (LIII) can be prepared from anintermediate of formula (XII-a) following the condensation reaction witha reagent of formula L—C(═X)—L (III) as described for the preparation of(I) from (II) and (III). The benzodiazepin-7-ones (LIII) can be reducedto benzodiazepines of formula (VI), wherein R⁶ and R⁷ are both hydrogen,said intermediates being represented by formula (VI-c), with a complexmetal hydride, e.g. lithium aluminum hydride and the like in a suitablereaction-inert solvent such as, for example, 1,2-dimethoxyethane,1,1′-oxybis(2-methoxyethane), 2,5,8,11-tetraoxadodecane, methoxybenzeneand the like solvents. In order to enhance the rate of said reductionreaction, it may be advantageous to employ an excess of the reducingreagent and to conduct said reaction at an enhanced temperature, inparticular the reflux temperature of the reaction mixture.

The thus obtained benzodiazepines of formula (VI-c) can bedehydrogenated to intermediates of formula (LIV). Said dehydrogenationcan be carried out by oxidation of (VI-c) with permanganate or withmanganese(IV)oxide in a suitable reaction-inert solvent such as, forexample, water, an alcohol, e.g. methanol, ethanol and the like, anether, e.g. 1,1′-oxybisethane, tetrahydrofuran and the like or a mixtureof such solvents. Or alternatively, the imine (LIV) may also be obtainedby reaction with nickel, platinum or chromium catalysts; or in thepresence of easily reducible substances such as sulfur, amyldisulfide,selenium or sodium amide in liquid ammonia

The benzodiazepines of formula (VI) wherein R⁷ is hydrogen and R⁶ ismethyl, said intermediates being represented by formula (VI-a), can beprepared from intermediates of formula (LIV) by reaction withorganometallic compounds of formula CH₃—M, wherein M represents a metalgroup such as, for example, lithium, halo magnesium, copper lithium andthe like, in a reaction-inert solvent like an ether, e.g.tetrahydrofuran, 1,1′-oxybisethane, 1,2-dimethoxyethane and the like; ahydrocarbon, e.g. hexane, benzene, methylbenzene and the like, or amixture thereof.

The benzodiazepines of formula (VI), wherein R⁶ and R⁷ are both methyl,said intermediates being represented by formula (VI-b), can be obtainedin a similar way. Dehydrogenation of (VI-a) yields an imine, which canbe converted to the 7-dimethylbenzodiazepine (VI-b) with organometalliccompounds of formula CH₃—M, following the same procedures as describedhereinabove for the preparation of (VI-a) from (VI-c).

The intermediates of formula (VI), wherein X is S, said intermediatesbeing represented by formula (VI-b-2), may be prepared by thionation ofan intermediate of formula (VI-b-1) following the procedures describedhereinabove for the preparation of the compounds of formula (I-b-2) from(I-b-1).

The intermediates of formula (XI) wherein R^(1H L and R) ⁷ are bothhydrogen, said intermediates being represented by (XI-a) can also beobtained by reacting an appropriately substituted nitrobenzene (LV) anda diamino reagent of formula (LVI). Herein Y is either hydrogen or aremovable protective group such as, for example, C-1-6alkylcarbonyl,e.g. acetyl, trichloroacetyl and the like, a benzyl group, aC₁₋₆alkyloxycarbonyl group, e.g. 1,1-dimethylethyloxycarbonyl, and thelike groups commonly used to protect an amino group.

Said reaction may conveniently be conducted by condensing the diaminoreagent of formula (LVI) with the nitrobenzene of formula (LV),optionally removing the protective group by alkline or acid hydrolysisor by catalytic hydrogenation and reducing the thus obtainedintermediate (LVII). Said condensation reaction can conveniently beconducted in a suitable reaction-inert solvent such as, for example, analkanol, e.g. methanol, ethanol, 2-propanol, 1-butanol and the like; anaromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene andthe like; a halogenated hydrocarbon, e.g. trichloromethane,tetrachloromethane and the like; an ether, e.g. tetrahydrofuran,1,4-dioxane, 1,1′-oxybisbutane, 1,1′-oxy(2-methoxyethane) and the like;a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; a dipolaraprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide,dimethyl sulfoxide and the like; or a mixture of such solvents. It maybe appropriate to add a base such as an alkali metal or earth alkalinemetal carbonate, e.g. sodium carbonate, sodium hydrogen carbonate andthe like, to the reaction mixture. Said condensation reaction canconveniently be conducted at an elevated temperature, in particular atthe reflux temperature of the reaction mixture. Said reductions in theabove procedure may conveniently be conducted by reacting theintermediate imines with a suitable reductive reagent such as, forexample, sodium borohydride, sodium cyanoborohydride and the likereductive reagents.

The intermediates of formula (XI-a) wherein R³ and R⁷ are both H, saidintermediates being represented by formula (XI-a-α), can also beprepared by reacting a substituted nitrobenzene (LV) with an amide offormula (LVIII). The thus obtained intermediates can be further reducedto intermediates of formula (XI-a-α) following procedures describedhereinabove for the preparation of (XI-a).

The compounds of formula (I) and the above described intermediates canalso be converted into each other following art-known procedures offunctional group transformation. Some examples of such procedures arecited hereinafter. The compounds of formula (I) wherein R⁴ or R⁵ is anitro group can be obtained following art-known nitration procedures, asdescribed hereinbefore (reaction step B of scheme 1). The compounds offormula (I) wherein R⁴ or R⁵ is a nitro substituent can be convertedinto the corresponding amines by stirring and, if desired, heating thestarting nitro compounds in hydrazine hydrate in the presence of acatalyst like Raney-nickel or in a hydrogen containing medium in thepresence of an appropriate catalyst such as, for example,platinum-on-charcoal, Raney-nickel and the like catalysts or followingother methods as described hereinbefore (reaction step A of scheme 1).Suitable solvents are, for example, methanol, ethanol and the like.Amino groups may be alkylated or acylated following art-known proceduressuch as, for example, N-alkylation, N-acylation, reductive N-alkylationand the like methods. The compounds of formula (I) wherein R⁴ or R⁵ is ahalo group can be obtained by halogenation of the correspondingcompounds wherein R⁴ or R⁵ is hydrogen in a suitable reaction-inertsolvent such as carbon-disulfide, dichloromethane, trichloromethane andthe like. Suitable halogenating reagents are for example,N-bromosuccinimide, chlorine, bromine and the like. In order to preventside reactions, other reactive functionalities may be protected.Suitable protective groups are for example alkyloxycarbonyl groups liket-butyloxycarbonyl, benzyloxycarbonyl and the like. The compounds offormula (I) wherein R⁴ or R⁵ is halo may be converted into compoundswherein R⁴ or R⁵ is hydrogen following art-known hydrogenolysisprocedures, e.g. by stirring and, if desired, heating the startingcompounds in a suitable reaction-inert solvent in the presence ofhydrogen and an appropriate catalyst such as, for example,palladium-on-charcoal and the like catalysts.

In all of the foregoing reaction schemes, the chemical designation ofthe intermediates defines the mixture of all possible stereochemicallyisomeric forms; mixtures of a number of possible stereochemicallyisomeric forms such as, for example, diastereomeric mixtures,enantiomeric mixtures, e.g. racemates and enriched enantiomericmixtures; and the enantiomerically pure isomeric forms of the basicmolecular structure.

Stereochemically isomeric forms of the intermediates described in theforegoing reaction schemes and of the compounds of formula (I) may beobtained by the application of art-known procedures. For example,diastereoisomers may be separated by physical separation methods such asdestillation, selective crystallization, chromatographic techniques,e.g. counter current distribution, liquid chromatography and the liketechniques. Pure enantiomers may be obtained by separating thecorresponding racemates for example, by the selective crystallization oftheir diastereomeric salts with optically active resolving agents,chromatography of diastereomeric derivates, chromatography of theracemate over a chiral stationary phase and the like techniques.Alternatively, enantiomerically pure forms can conveniently be obtainedfrom the enantiomerically pure isomeric forms of the appropriatestarting materials, provided that the subsequent reactions occurstereospecifically. Particularly interesting enantiomerically purestarting materials for use in the foregoing reaction schemes areaminoacids and/or substituted derivatives thereof, having the formulaR^(1H)NH—CH(R²)—COOR (XL), the corresponding aminoalkanolsR^(1H)NH—CH(R²)—CH(R³)OH (XXVII) and diamino reagentsR^(1H)NH—CH(R²)—CH(R³)—NH₂ (XXVI).

The compounds of formula (I) show antiretroviral properties. Untilrecently, retroviruses were considered to be the-pathogenic agents in anumber of non-human warm-blooded animal diseases only, unlike viruseswhich have been known for quite some time to be the cause of a largenumber of diseases in warm-blooded animals and humans alike. However,since it has been established that a retrovirus, Human ImmunodeficiencyVirus (HIV), also known as LAV, HTLV-III or ARV, is the etiologicalagent of Acquired Immune Deficiency Syndrome (AIDS) in humans,retroviral infections and the treatment of subjects suffering therefromhave received the utmost attention. The HIV virus preferentially infectshuman T 4 cells and destroys them or changes their normal function,particularly the coordination of the immune system. As a result, aninfected patient has an everdecreasing number of T 4 cells, whichmoreover behave abnormally. Hence, the immunological defense system isunable to combat infections and neoplasms and the HIV infected subjectusually dies by opportunistic infections such as pneumonia, or bycancers, rather than as a direct result of HIV infections. Otherconditions associated with HIV infection include thrombo-cytopaenia,Kaposi's sarcoma and infection of the central nervous systemcharacterized by progressive demyelination, resulting in dementia andsymptoms such as, progressive dysarthria, ataxia and disorientation. HIVinfection further has also been associated with peripheral neuropathy,progressive generalized lymphadenopathy (PGL) and AIDS-related complex(ARC). The antiretroviral and especially the anti-HIV properties of thecompounds of formula (I) suggest said compounds to be usefulantiretroviral chemotherapeutical agents for the prophylaxis ortreatment of warm-blooded animals suffering from viral infections, moreparticularly for the treatment of humans infected by HIV virus.

Due to their antiretroviral properties, the compounds of formula (I),their pharmaceutically acceptable salts and the stereochemicallyisomeric forms thereof, are useful in the treatment of warm-bloodedanimals infected with retroviruses or for the prophylaxis of saidwarm-blooded animals. The compounds of the present invention may beespecially useful in the treatment of warm-blooded animals infected withretroviruses whose existence is mediated by, or depends upon, the enzymereverse transcriptase, because these compounds inhibit the enzymereverse transcriptase.

Examples of human retroviral infections include HIV and HTLV-I (humanT-lymphotropic virus type I), causing leukemia and lymphoma. As anexample of non-human animal retroviral infection there may be mentionedFeLV (feline leukemia virus) which causes leukemia and immunodeficiency.Conditions which may be prevented or treated with the compounds of thepresent invention, especially conditions associated with HIV and otherpathogenic retroviruses, include AIDS, AIDS-related complex (ARC),progressive generalized lymphadenopathy (PGL), as well as chronic CNSdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

In view of their antiretroviral activity, the subject compounds may beformulated into various pharmaceutical forms for administrationpurposes. To prepare the pharmaceutical compositions of this invention,an effective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not cause a significantdeleterious effect to the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acidaddition salts of (I) due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The present invention is also related with a method of treatingretroviral diseases in warm-blooded animals suffering from saidretroviral diseases by administering an effective antitroviral amount ofa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereoisomeric form thereof. Those of skill in the treatmentof viral diseases could easily determine the effective antiviral amountfrom the test results presented herein. In general it is contemplatedthat an effective amount would be from 0.1 mg/g to 200 mg/kg bodyweight, and in particular from 1 mg/kg to 50 mg/kg body weight. It maybe appropriate to administer the required dose as two, three, four ormore sub-doses at appropriate intervals throughout the day. Saidsub-doses may be formulated as unit dosage forms, for example,containing 1 to 1000 mg, and in particular 5 to 200 mg of activeingredient per unit dosage form.

The following examples are intended to illustrate and not to limit theinvention in all its aspects. Unless otherwise stated, all parts thereinare by weight.

EXPERIMENTAL PART A. Preparation of the Intermediates Example 1

a) A mixture of 11.7 parts of methyl 2-bromo-3-nitrobenzoate, 8.1 partsof 1,2-ethanediamine mononohydrate and 40 parts of 1-butanol was stirredfor ½ hour at reflux temperature. The reaction mixture was evaporatedand the residue was diluted with 50 parts of water. The precipitate wasfiltered off and washed with water and 2-propanol. It was thenrecrystallized from 2-methoxyethanol, yielding 6.5 parts of2,3,4,5-tetrahydro-9-nitro-1H-1,4-benzodiazepin-5-one; m.p. 191-195° C.(interm. 1).

b) To a mixture of 6.3 parts of intermediate 1 in 60 parts ofN,N-dimethylformamide there were added 3.7 parts of 2-methyl-2-propanolpotassium salt and, after stirring for 15 min at 50° C., 4.2 parts ofchloromethylbenzene. Stirring at 50° C. was continued for 1 hour. Thereaction mixture was evaporated and the residue was diluted with 50parts of water. The product was extracted with trichloromethane (3×75parts) and the combined extracts were dried, filtered and evaporated.The residue was purified by column chromatography (silica gel; CHCl₃/C₂H₅OH 98:2). The eluent of the desired fraction was evaporated and theresidue was crystallized from 2-propanol. The product was filtered offand dried, yielding 3.3 parts of4-(phenylmethyl)-2,3,4,5-tetrahydro-9-nitro-1H-1,4-benzodizepin-5-one;m.p. 129-132° C. (interm. 2).

Example 2

a) To a stirred suspension of 414 parts of 2-bromo-3-nitrobenzoic acidin 653 parts of methylbenzene there were added 440 parts of thionylchloride. The whole was refluxed for 6 hours, cooled and left overnight.The reaction mixture was treated with activated charcoal, filtered overdiatomaceous earth and evaporated. The residual oil was triturated with396 parts of hexane (2×). The product was filtered off, washed withhexane and dried, yielding 363 parts (81.7%) of 2-bromo-3-nitrobenzoylchloride (interm. 3).

b) A mixture of 14.9 parts of intermediate 3; 9.07 parts of2,3-butanediamine dihydrochloride, 17.9 parts of sodium carbonate and146 parts of 1-butanol was refluxed overnight. After cooling, thereaction mixture was filtered and the filtrate was evaporated. Theresidual oil was partitioned between water and dichloromethane. Theorganic layer was dried, filtered and evaporated. The residue wascrystallized from ethyl acetate, yielding 5.64 parts (42.6%) oftrans-1,2,3,4-tetrahydro-2,3-dimethyl-9-nitro-5H-1,4-benzodiazepin-5-one;mp. 169.5° C. (interm. 4).

c) To a mixture of 7.76 parts of intermediate 4 and 445 parts oftetrahydrofuran there were added 104 parts of a solution of boranetetrahydrofuran complex in tetrahydrofuran 1M. After refluxing for 4days, there were added 50 parts of water and 150 ml of NaOH (3N).Refluxing was continued for 3 hours. The organic layer was separated,washed with NaCl (sat.) (2×), dried, filtered and evaporated. Theresidue was purified by flash column chromatography (silica gel;CH₂Cl₂/CH₃OH/NH₄OH 93:7:0.1). The eluent of the desired fraction wasevaporated, yielding 0.4 parts (5.5%) of(2,3-trans)-2,3,4,5-tetrahydro-2,3-dimethyl-9-nitro-1H-1,4-benzodiazepine(interm. 5).

d) A mixture of 0.34 parts of intermediate 5; 0.23 parts of1-bromo-3-methyl-2-butene, 0.33 parts of sodium carbonate, 0.26 parts ofpotassium iodide and 9.4 parts of N,N-dimethylformamide was stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with waterand NaCl (sat.), dried, filtered and evaporated. The residue waspurified by flash column chromatography (silica gel; CH₂Cl₂/CH₃OH/NH₄OH93:7:0.1). The eluent of the desired fraction was evaporated and theresidual oil crystallized on standing, yielding 0.18 parts (40.4%) of(2,3-trans)-2,3,4,5-tetrahydro-2,3-dimethyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4benzodiazepine(interm. 6).

e) To a cooled (0° C.) mixture of 0.18 parts of intermediate 6 and 8.9parts of tetrahydrofuran there were added 0.095 parts of lithiumaluminum hydride. The whole was allowed to warm to room temperature andwas then refluxed for 45 min. To the reaction mixture there were addedsuccessively 100 parts of water, 300 ml of NaOH (3N) and 100 parts ofwater. After stirring for ½ hour, the mixture was filtered, dried,filtered and evaporated, yielding 0.17 parts (100%) of(2,3-trans)-2,3,4,5-tetrahydro-2,3-dimethyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 7).

Example 3

a) To a slightly heated mixture of 37.3 parts of intermediate 3 and 142parts of 1,1′-oxybisethane there was added a solution of 35.0 parts of(diethyl propane-dioato-O″, O′″) ethoxy magnesium in 92.3 parts of1,1′-oxybisethane under an Argon atmosphere. Heating was continued for1½ hours. Then there was added a solution of 19 parts of sulfuric acidin 150 parts of water. The organic layer was separated, washed with NaCl(sat.), dried, filtered and evaporated. The residue was refluxed for 6hours in a mixture of 28 parts of water, 4.41 parts of acetic acid and9.75 parts of sulfuric acid. After cooling, the whole was basified withNaOH (3N) and extracted with 1,1′-oxybisethane. The extract was dried,filtered and evaporated, yielding 29.9 parts (86.9%) of1-(2-bromo-3-nitro-phenyl)ethanone (interm. 8).

b) To 29.6 parts of intermediate 8 there were added 12.9 parts of sodiumcarbonate and 486 parts of 1-butanol under an Argon atmosphere. Thewhole was heated till complete solution and then there were added 9.0parts of 1,2-propanediamine. After refluxing for 4 hours, the reactionmixture was evaporated. The residue was partitioned betweendichloromethane and water. The organic layer was separated, dried,filtered and evaporated. The residue was purified by columnchromatography (HPLC; silica gel; CH₃COCH₃/hexane 20:80). The eluent ofthe desired fraction was evaporated, yielding 11.4 parts (43.0%) of2,3-dihydro-3,5-dimethyl-9-nitro-1H-1,4-benzo-diazepine (intern. 9).

c) A mixture of 11.35 parts of intermediate 9; 79 parts of methanol and3.9 parts of sodium cyanotrihydroborate was stirred overnight at roomtemperature under an Argon atmosphere. There were added an additional0.2 parts of sodium cyanotrihydroborate and some methanol saturated withhydrochloric acid. The reaction mixture was acidified to pH 1 withhydrochloric acid (3N). The solvent was evaporated and the base was setfree. The residue was purified by column chromatography (HPLC; silicagel; CH₃COCH₃/hexane 1:1). The eluent of the desired fraction wasevaporated, yielding 2.3 parts (20.1%) ofcis-2,3,4,5-tetrahydro-3,5-dimethyl-9-nitro 1H-1,4-benzodiazepine; mp.62.0° C. (interm. 10).

d) To 2.18 parts of intermediate 10 there were added successively 1.6parts of sodium carbonate, 1.64 parts of potassium iodide, 23.5 parts ofN,N-dimethylformamide and a solution of 1.81 parts of1-bromo-3-methyl-2-butene in 23.5 parts of N,N-dimethylformamide. Afterstirring overnight at room temperature, the reaction mixture wasevaporated. The residue was partitioned between dichloromethane andK₂CO₃ (aq.). The organic layer was separated, dried, filtered andevaporated. The residue was converted into the (E)-2-butenedioate (2:1)salt in 2-propanol. The product was filtered off and dried, yielding2.82 parts (82.4%) ofcis-2,3,4,5-tetrahydro-3,5-dimethyl4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine(E)-2-butenedioate (2:1); mp. 128.0° C. (interm. 11).

e) To a cooled (ice-bath) mixture of 1.73 parts of lithium aluminumhydride and 44.5 parts of tetrahydrofuran there was added slowly asolution of 3.28 parts of intermediate 11 in 35.6 parts oftetrahydrofuran under an Argon atmosphere. The whole was stirred at 0°C. for ½ hour, at room temperature for 3 hours and at reflux temperaturefor 7 hours. After cooling, there were added slowly 1.7 parts of water,1.7 ml of NaOH (3N), 5.1 parts of water and 89 parts of tetrahydrofuran.The mixture was filtered and the precipitate was washed with 178 partsof hot tetrahydrofuran. The combined filtrates were evaporated, yielding2.82 parts (96.2%) ofcis-2,3,4,5-tetrahydro-3,5-dimethyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 12).

In a similar manner there were also prepared:

2,3,4,5-tetrahydro-5-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 13);

2,3,4,5-tetrahydro-5-methyl-4-propyl-1H-1,4-benzodiazepin-9-amine(interm. 14);trans-2,3,4,5-tetrahydro-3,5-dimethyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9amine(interm. 15);

(2,5-trans)-2,3,4,5-tetrahydro-2,5-dimethyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interr. 16);

(2,5-cis)-2,3,4,5-tetrahydro-2,5-dimethyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 17); and

[3S-(3α,5β)]-7-chloro-2,3,4,5-tetrahydro-3,5-dimethyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 18).

Example 4

To a solution of 1.34 parts of7-chloro-2,3,4,5-tetrahydro-5-methyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine(prepared as intermediate 11) in methanol there were added 0.49 parts ofRaney nickel. To the resulting suspension there was added dropwise asolution of 1.09 parts of hydrazine in a small amount of methanol, atreflux temperature and under an Argon atmosphere. Refluxing wascontinued for 1½ hour. After cooling, the catalyst was filtered off andthe filtrate was evaporated, yielding 1.3 parts (100%) of7-chloro-2,3,4,5-tetrahydro-5-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 19).

Example 5

a) A mixture of 2.6 parts of methyl 2-bromo-3-nitrobenzoate, 1.75 partsof 2-[(phenylmethyl)amino]propanamine, 1.06 parts of sodium carbonateand 8 parts of 1-butanol was stirred for ½ hour at reflux temperature.The reaction mixture was evaporated and the residue was diluted with 20parts of water. The product was extracted with trichloromethane (2×30parts) and the combined extracts were dried, filtered and evaporated.The residue was converted into the monohydrochloride salt in 2-propanol.The product was filtered off, washed with 2-propanol and dried, yielding3.4 parts (89.5%) of methyl2-[2-[(phenylmethyl)amino]propylamino]-3-nitrobenzoatemonohydrochloride; mp. 204° C. (internm 20).

b) A mixture of 3.8 parts of intermediate 20; 15 parts of NaOH (2 N) and4 parts of 2-propanol was stirred for 1 hour at reflux temperature.While refluxing, there was added a solution of 3 parts of concentratedhydrochloric acid and 5 parts of water. After cooling, the precipitatedproduct was filtered off, washed with water and recrystallized fromacetic acid, yielding 3 parts (82%) of2-[[2-methyl-2-[(phenylmethyl)amino]ethyl]amino]-3-nitrobenzoic acid;mp. 227° C. (interim 21).

c) A mixture of 189.3 parts of intermediate 21; 400 parts of thionylchloride and 400 parts of methylbenzene was stirred for 2 hours atreflux temperature. The reaction mixture was evaporated and the residuewas taken up in 600 parts of methylbenzene. The whole was neutralizedwith NaHCO₃ (aq.). The organic layer was separated, dried, filtered andconcentrated. The residue was left at room temperature. The precipitatewas filtered off, washed with 2-propanol and 1,1′-oxybisethane anddried, yielding 123.5 parts of product. The mother liquor was evaporatedand the residue was recrystallized from boiling 2-propanol. The productwas filtered off at room temperature, washed with 2-propanol and1,1′-oxybisethane and dried, yielding an additional 28 parts of product.The combined crops were recrystallized from ethanol, yielding 137 parts(85%) of2,3,4,5-tetrahydro-3-methyl-9-nitro-4-(phenylmethyl)-1H-1,4-benzodiazepin-5-one;mp. 125° C. (interm. 22).

d) To a stirred and refluxing suspension of 14 parts of lithium aluminumhydride in 40 parts of benzene and 50 parts of tetrahydrofuran there wasadded a solution of 20.2 parts of intermediate 22 in 200 parts oftetrahydrofuran. Stirring at reflux temperature was continued for 2.5hours. After cooling on ice, there were added successively water, NaOH15% and water. The whole was filtered and the filtrate was evaporated.The residue was co-evaporated with 40 parts of methylbenzene, yielding19.8 parts (87.6%) of9-amino-2,3,4,5-tetrahydro-3-methyl-4-(phenylmethyl)-1H-1,4-benzodiazepine(which was used without further purification in the next reaction step)(interm. 23).

Example 6

a) To a stirred and cooled (−12° C.) mixture of 9.10 parts of2-amino-3-nitrobenzoic acid, 6.95 parts of methyl L-α-alaninemonohydrochloride, 13.50 parts of 1-hydroxy-1H-1,2,4-benzotriazolemonohydrate and 178 parts of tetrahydrofuran there were addedportionwise 5.05 parts of N-methylmorpholine and, after 5 min, 10.3parts of N,N′-methanetetraylbis[cyclohexanamine] under an argonatmosphere. Stirring was continued for 5½ hours at −12° C. and for 15hours at room temperature. After cooling to 0° C. for ½ hour, thereaction mixture was filtered and the filtrate was evaporated. Theresidue was partitioned between ethyl acetate and a saturated sodiumhydrogen carbonate solution. The organic layer was separated, washedwith NaHCO₃ (sat.), dried, filtered and evaporated. The residue wastriturated with hexane. The product was filtered off and dried, yielding13.08 parts (97.9%) of(−)-methyl(S)-2-[(2-amino-3-nitrobenzoyl)amino]propanoate; mp. 132.9° C.(interm. 24).

b) A mixture of 12.58 parts of intermediate 24; 3.50 parts ofpalladium-on-charcoal catalyst 10% and 158 parts of ethanol washydrogenated in a Parr apparatus for 4 hours at room temperature and apressure of 3.1 10⁵ Pa. The catalyst was filtered off over diatomaceousearth and the filtrate was evaporated. The residue was placed underreduced pressure (3.3 10³ Pa) and stirrd at 150° C. for 10 min and at202° C. for 40 min. After cooling, the solid was triturated withethanol. The product was filtered off, washed with ethanol and1,1′-oxybisethane and dried, yielding 5.58 parts (57.7%) of(+)-(S)-9-amino-3,4-dihydro-3-methyl-1H-1,4-benzodiazepine-2,5-dione(interm. 25).

c) To a suspension of 5.55 parts of lithium aluminum hydride in 154.5parts of 1,4-dioxane there were added 5.00 parts of intermediate 25under an argon atmosphere. After refluxing for 5 hours and subsequentcooling to 10° C., there were added successively 5.55 parts of water,9.16 parts of NaOH (15%) and 16.65 parts of water. The whole was stirredfor 2 hours and then filtered. The precipitate was washed with 178 partsof hot tetrahydrofuran and 133 parts of hot dichloromethane. Thecombined filtrates were dried, filtered and evaporated. The residue waspoured into a solution of 7.36 parts of N-methylmorpholine in 133 partsof dichloromethane. The whole was added dropwise to a solution of 4.82parts of trichloromethyl chloroformate in 160 parts of dichloro-methaneat 0° C. under an argon steam. Stirring at 0° C. was continued for 10min. After warming to room temperature, the reaction mixture wasevaporated and there were added 70 parts of an aqueous 1,4-dioxanesolution (15%) to the residue. The mixture was heated on a steam-bathfor 45 min under a nitrogen stream, cooled and extracted withdichloromethane (2×66.5 parts). The aqueous layer was filtered andbasified with concentrated ammonium hydroxide. The precipitate wasfiltered off, washed with cold water, dried and triturated with2-propanol (2×), yielding 1.59 parts (32.1%) of(+)-(S)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 206.5° C. (interm. 26).

In a similar manner there were also prepared:

(−)-(R)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 207.8° C. (interm. 27);

4,5,6,7-tetrahydro-5,8-dimethylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 244.8° C. (interm. 28); and

(+)-(S)-4,5,6,7-tetrahydro-5,8-dimethylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 207.8° C. (interm. 29).

d) To a cooled (−35° C.) mixture of 7.4 parts of intermediate 26 and 395parts of acetonitrile there were added 24.8 parts of(1,1-dimethylethoxy)formic acid anhydride and 0.45 parts ofN,N-dimethyl-4-pyridinamine. The whole was left for 12 hours at roomtemperature and was then evaporated. The residue was purified by flashcolumn chromatography (silica gel; CH₂Cl₂/CH₃OH 99:1). The eluent of thedesired fraction was evaporated and the residue was stirred for 3 hoursin a mixture of 79 parts of methanol and 1.5 parts of potassiumcarbonate. The solvent was evaporated and the residue was partitionedbetween ethyl acetate and water. The organic layer was separated, dried,filtered and evaporated, yielding 6.4 parts (57.5%) of(1,1-dimethylethyl)(S)-1,2,4,5,6,7-hexahydro-5-methyl-2-oxoimidazo[4,5,1-jk][1,4]benzodiazepine-6-carboxylate(interm. 30).

e) 5.43 parts of intermediate 30 and 224 parts of trichloromethane werecombined at room temperature under argon. After cooling to −35° C.,there were added 2.29 parts of N-bromosuccinimide. The whole was kept at−35° C. for 6 hours, allowed to warm to room temperature and left for 12hours. The reaction mixture was evaporated and the residue was purifiedby column chromatography (LC; RP). The eluent of the desired fractionwas evaporated, yielding 0.5 parts (7.3%) of (1,1-dimethylethyl)(+)-(S)-10-bromo-1,2,4,5,6,7-hexahydro5-methyl-2-oxoimidazo[4,5,1-jk][1,4]benzodiazepine-6-carboxylate;mp. 228.7° C.; [α]_(D) ²⁵=+75.8° (conc.=0.55 in methanol) (interm. 31).

f) 5.43 parts of intermediate 30 and 224 parts of trichloromethane werecombined at room temperature under argon. After cooling to −35° C.,there were added 2.29 parts of N-bromosuccinimide. The whole was kept at−35° C. for 6 hours, allowed to warm to room temperature and left for 12hours. The reaction mixture was evaporated and the residue was purifiedby column chromatography (LC; RP). The eluent of the desired fractionwas evaporated, yielding 2.10 parts (30.7%) of (1,1-dimethylethyl)(−)-(S)-8-bromo-1,2,4,5,6,7-hexahydro-5-methyl-2-oxoimidazo[4,5,1-jk][1,4]benzodiazepine-6-carboxylate;mp. 228.6° C.; [α]_(D) ²⁵=−60.0° (conc.=0.30 in methanol) (interm. 32).

Example 7

a) To a cooled (−5° C.) mixture of 20.0 parts of2-amino-3-nitro-5-(trifluoromethyl)benzoic acid, 11.17 parts ofmethyl(S)-alanine monohydrochloride, 21.62 parts of1-hydroxy-1H-1,2,4-benzotriazole monohydrate and 356 parts oftetrahydrofuran under argon there were added 8.1 parts ofN-methylmorpholine and, after stirring for 10 min 16.5 parts ofN,N-methanetetraylbis[cyclohexanamine]. Stirring was continued for 1hour at −5° C. and overnight at room temperature. After cooling on ice,the reaction mixture was filtered and the filtrate was evaporated. Theresidue was dissolved in dichloromethane and this solution was washedwith NaHCO₃ (aq.), dried, filtered and evaporated. The residue wasrecrystallized from methylcyclohexane (2×), yielding 19.1 parts (71.2%)of methyl(S)-N-[2-amino-3-nitro-5-(trifluoromethyl)benzoyl]alanine; mp.136.4° C. (interm. 33).

b) A mixture of 26.1 parts of intermediate 33 and 395 parts of ethanolwas hydrogenated at 3.4 10⁵ Pa and at room temperature with 9.1 parts ofpalladium-on-charcoal catalyst 10%. After 2 hours, the catalyst wasfiltered off and the filtrate was evaporated. The residue was purifiedby column chromatography (silica gel; CH₂Cl₂). The eluent of the desiredfraction was evaporated and the residue was crystallized from a mixtureof methylbenzene and methylcyclohexane (2:1). The product was filteredoff and dried, yielding 5.66 parts (23.8%) ofmethyl(S)-N-[2,3-diamino-5-(trifluoromethyl)benzoyl]alanine; mp. 96.0°C. (interm. 34).

c) A mixture of 20.56 parts of intermediate 34; 19.6 parts of pyridineand 20 parts of pyridine monohydrochloride was refluxed for 23 hoursunder argon. The reaction mixture was partitioned betweendichloromethane and NaHCO₃ (aq.). After filtration, the organic layerwas separated, dried, filtered and evaporated. To the residue there wereadded 399 parts of dichloromethane. The precipitate was filtered off,yielding 6.35 parts (34.5%) of product. The filtrate was evaporated andthe residue was purified by flash column chromatography (silica gel;CH₂Cl₂/CH₃OH 19:1). The eluent of the desired fractions was evaporatedand the residue was crystallized from acetonitrile, yielding anadditional 0.32 parts (1.74%) of product. Total yield: 6.67 parts(36.2%) of(S)-9-amino-3,4-dihydro-3-methyl-7-(trifluoromethyl)-1H-1,4-benzodiazepine-2,5-dione;mp. 275.3° C. (interm. 35).

d) To a cooled (0° C.) mixture of 3.39 parts of sodium tetrahydroborateand 38.3 parts of 1,2-dimethoxyethane under argon, there were addeddropwise 8.32 parts of titanium-(IV)chloride and a solution of 3.0 partsof intermediate 35 in 13.9 parts of 1,2-dimethoxyethane. The whole wasstirred for 6 days at room temperature and was then partitioned betweenNH₄OH (conc.) and dichloromethane. The mixture was filtered and theorganic layer was separated. The precipitate was washed withdichloromethane and the combined dichloromethane layers were evaporated.The residue was stirred in 40 ml of HCl (3N) for 1 hour. After basifyingwith NaOH (3N), the product was extracted with dichloromethane. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel ; CH₂Cl₂/CH₃OH 9:1). The eluent of thedesired fraction was evaporated, yielding 1.14 parts (42.3%) of(S)-2,3,4,5-tetrahydro-3-methyl-7-(trifluoromethyl)-1H-1,4-benzodiazepin-9-amine(interm. 36).

e) To a cooled (0° C.) solution of 1.06 parts of intermediate 36; 1.32parts of N-methylmorpholine and 53.2 parts of dichloromethane underargon, there was added dropwise a solution of 0.86 parts oftrichloromethyl chloroformate in 26.6 parts of dichloromethane. Afterstirring for 12 min at 0° C., the reaction mixture was washed withNaHCO₃ (sat.), dried, filtered and evaporated. The residue was purifiedtwice by flash column chromatography (silica gel; CH₂Cl₂/CH₃OH 98:2;CH₂Cl₂/CH₃OH 99.5:0.5). The eluent of the desired fraction wasevaporated and the residue was heated on a steam bath for 1½ hours in amixture of water and 1,4-dioxane (85:15). The whole was evaporated andthe residue was dissolved in dichloromethane. This solution was washedwith NaHCO₃, dried, filtered and evaporated, yielding 0.75 parts (63.9%)of(S)-4,5,6,7-tetrahydro-5-methyl-9-(trifluoromethyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one(interm 37).

Example 8

a) To a stirred solution of 11.8 parts of 1-propanamine in 24.9 parts of1,1′-oxybis ethane there was added dropwise a solution of 18.1 parts ofethyl 2-bromopropanoate in 24.9 parts of 1,1′-oxybisethane. Afterstirring for 72 hours at room temperature, the reaction mixture wasfiltered and the filtrate was rinsed with 1,1′-oxybisethane. Thecombined 1,1′-oxybisethane layers were evaporated, yielding 15.9 parts(100%) of ethyl N-propylalanine as a residue (interm. 38).

b) A mixture of 9.90 parts of 2-amino-3-nitrobenzoic acid and 32.4 partsof thionyl chloride was stirred for 15 min at reflux temperature underargon. The excess of thionyl chloride was evaporated, yielding 10.8parts (100%) of 2-amino-3-nitrobenzoyl chloride (interm. 39).

c) To a stirred and cooled (0° C.) solution of 8.65 parts ofintermediate 38 and 5.52 parts of N,N-diethylethanamine in 53.2 parts ofdichloromethane there was added dropwise a suspension of 10.83 parts ofintermediate 39 in 119.7 parts of dichloromethane under argon. Stirringwas continued for 5 min at 0° C. and for 1 hour at room temperature. Thereaction mixture was washed successively with water, NaHCO₃ (sat.),citric acid (2N) and again NaHCO₃ (sat.) and was then dried, filteredand evaporated, yielding 19.14 parts (100%) of ethylN-(2-amino-3-nitrobenzoyl)-N-propylalanine (interm. 40).

d) A solution of 17.5 parts of intermediate 40 in 80 parts of ethanolwas hydrogenated at 3.5 10⁵ Pa and at room temperature with 2.0 parts ofpalladiumon-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off over diatomaceousearth and the filtrate was evaporated. The residual oil was heated invacuo (3.3 10³ Pa) in an oil bath (100° C.) for 1½ hours. After cooling,the oil was purified by column chromatography (silica gel ; CH₂Cl₂/CH₃OH20:1). The eluent of the desired fraction was evaporated, yielding 4.6parts (34.4%) of9-amino-3-methyl-4-propyl-3H-1,4-benzodiazepine-2,5(1H,4H)-dione(interm. 41).

e) To a stirred and cooled (0° C.) suspension of 1.28 parts of lithiumaluminum hydride in 52 parts of 1,2-dimethoxyethane under argon, therewere added dropwise 1.39 parts of intermediate 41. Stirring wascontinued for 2 hours at 0° C. and for 72 hours at reflux temperature.After cooling, there were added successively a solution of 1.3 parts ofwater and 3.6 parts of tetrahydrofuran, 1.3 parts of NaOH (15%) and 3.9parts of water. The whole was stirred for 1 hour and then filtered. Theprecipitate was refluxed for 5 min in 45 parts of tetrahydrofuran andfiltered off again. The combined filtrates were dried, filtered andevaporated, yielding 1.24 parts (100%) of2,3,4,5-tetrahydro-3-methyl-4-propyl-1H-1,4-benzodiazepin-9-amine(interm. 42).

Example 9

a) A mixture of 17.7 parts of 6-methyl-4H-3,1-benzoxazine-2,4(1H)-dione,15.0 parts of methyl 2-aminopropanoate monohydrochloride and 62.7 partsof pyridine was refluxed for 6 hours under argon. The reaction mixturewas cooled at −10° C. for 1 hour. The precipitate was filtered off,rinsed with water, triturated in ethanol and rinsed with ethanol and1,1′-oxybisethane, yielding 10.32 parts (50.5%) of3,4-dihydro-3,7-dimethyl-1H-1,4-benzodiazepine-2,5-dione (interm. 43).

b) To a cooled (0° C.) amount of 61.9 parts of concentrated nitric acidthere were added dropwise 9.50 parts of intermediate 43 under argon. Themixture was left at 0° C. for 1 hour and was then slowly added to 160parts of ice-water while stirring. The precipitate was filtered off,rinsed with water and dried overnight at room temperature, yielding 9.92parts (85.5%) of3,4-dihydro-3,7-dimethyl-9-nitro-1H-1,4-benzodiazepine-2,5dione (interm.44).

c) To a cooled (0° C.) suspension of 10.35 parts of lithium aluminumhydride in 305 parts of 1,2-dimethoxyethane there were added 9.71 partsof intermediate 44 under argon. After refluxing for 72 hours andsubsequent cooling, there were added successively a mixture of 10.35parts of water and 31 parts of tetrahydrofuran, 10.35 ml of NaOH (15%)and 31.05 parts of water. The whole was stirred for 1 hour and was thenfiltered. The precipitate was refluxed in tetrahydrofuran for 5 min andfiltered off again. The combined filtrates were dried, filtered andevaporated. The residual oil was immediately combined with a mixture of11.8 parts of N-methyhnorpholine and 79.8 parts of dichloromethane andthe whole was added to a mixture of 7.7 parts of trichloromethylchloroformate and 120 parts of dichloromethane at 0° C. under argon. Themixture was stirred for 5 min at 0° C. and evaporated. The residue washeated on a steam-bath for 1 hour in 100 ml of a mixture of water anddioxane (85:15) under argon. The solution was cooled, basified withNH₄OH and extracted with dichloromethane (2×46.6 parts). The combinedextracts were dried, filtered and evaporated. The residue was trituratedwith 2-propanol and recrystalie from 2-propanol. The product wasfiltered off, rinsed with 2-propanol and 1,1′-oxybisethane, yielding0.55 parts (6.5%) of4,5,6,7-tetrahydro-5,9-dimethylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 199.2° C. (interm. 45).

In a similar manner there were also prepared the intermediates listed inTable 1 hereinbelow.

TABLE 1

Int.No. R² R⁴ R⁵ Physical data 47 CH₃ 9-Cl H (±) ; mp. 199.0° C. 48 CH₃9-Cl H (+)-(S) ; mp. 202.2° C. [α]²⁰ _(D 0.98% CH) ₃ _(OH) = +72.6° 49CH₃ 9-Cl H (−)-(R) ; mp. 200.8° C. [α]²⁰ _(D 1.01% CH) ₃ _(OH) = −68.6°50 H 9-Cl H mp. 238-244° C. 51 CH₃ 9-F H (S) ; mp. 222.1° C. 52 CH₃ 9-Cl10-Cl (S)

Example 10

a) To a stirred suspension of 6.85 parts of intermediate 39 and 4.7parts of 1-amino-3-methyl-2-butanone monohydrochloride in 113 parts ofdichloromethane there was added dropwise a solution of 6.9 parts ofN,N-diethylethanamine in 20 parts of dichlormethane under a nitrogenatmosphere. Stirring was continued for 21 hours. The reaction mixturewas washed with water and the washings were re-extracted withdichloromethane. The combined dichloromethane layers were washed withwater, NaHCO₃ (sat.) and NaCl (sat.) and were then dried, filtered andevaporated. The residue was recrystallized from ethanol. The hotsolution was filtered and the filtrate was evaporated, yielding 6 parts(66.5%) of 2-amino-N-(3-methyl-2-oxobutyl)-3-nitrobenzamide (interm.53).

b) A mixture of 5.9 parts of intermediate 53; 2.37 parts ofpalladium-on-charcoal catalyst 10% and 119 parts of ethanol washydrogenated in a Parr apparatus at 3.6 10⁵ Pa for 50 hours. Thecatalyst was filtered off over diatomaceous earth, which was rinsed withethanol and dichloromethane. The combined filtrates were evaporated,yielding 4.64 parts (96.0%) of9-amino-3,4-dihydro-2-(1-methylethyl)-5H-1,4-benzodiazepin-5-one(interm. 54).

c) To a stirred suspension of 4.75 parts of intermediate 54 in 155 partsof 1,4-dioxane there were added 5.0 parts of lithium aluminum hydrideunder argon. The whole was heated at 90-110° C. for 6 days andsubsequently cooled on ice. There were added successively a mixture of 5parts of water and 22.3 parts of tetrahydrofuran, 5 ml of NaOH (3N) and15 parts of water. After stirring for 2 hours at 0° C., the mixture wasdried and filtered. The solid was washed with 266 parts of hotdichloromethane and the combined filtrates were evaporated, yielding 4.7parts (100%) of2,3,4,5-tetrahydro-2-(1-methylethyl)-1H-1,4-benzodiazepin-9-amine(interm. 55).

d) To a stirred and cooled (0° C.) solution of 4.51 parts oftrichloromethyl chloroformate in 133 parts of dichloromethane underargon, there was added dropwise a solution of 4.7 parts of intermediate55 and 7.0 parts of N-methylmorpoline in 66.5 parts of dichloromethane.Stirring was continued for 2½ hour at 0° C. The reaction mixture wasevaporated and the residue was heated on a steam-bath for 5 hours in amixture of 15 parts of water and 87.6 parts of 1,4-dioxane. Aftercooling, the mixture was washed with dichloromethane (3×) and thenbasified with NH₄OH. The product was extracted with dichloromethane (3×)and the extract was washed with water and NaCl (sat.), dried, filteredand evaporated. The residue was purified by flash column chromatography(silica gel; CH₂Cl₂/C₂H₅OH 96:4). The eluent of the desired fraction wasevaporated and the residue was triturated with acetonitrile. The productwas filtered off and dried in an Abderhalen (2-propanol reflux)overnight, yielding 0.67 parts (12.6%) of4,5,6,7-tetrahydro-4-(1-methylethyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 167.4° C. (interm. 56).

In a similar manner there were also prepared:

4,5,6,7-tetrahydro-4-propylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 160.7° C. (interm. 57); and

4,5,6,7-tetrahydro-4-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 220.2° C. (interm. 58).

Example 11

a) To a cooled (0° C.) suspension of 8.53 parts of lithium aluminumhydride in 392 parts of 1,2dimethoxyethane there were added dropwise20.19 parts of(S)-7-chloro-3,4-dihydro-3-methyl-1H-1,4-benzodiazepine-2,5-dione(prepared as intermediate 43) under argon. The mixture was left at roomtemperature for 3 hours and was then refluxed for 29 hours. Aftercooling to 0° C., there were added successively a mixture of 8.5 partsof water and 22.7 parts of tetrahydrofuran, 9.86 parts of NaOH (15%) and25.5 parts of water. The whole was stirred for 24 hours and was thenfiltered. The precipitate was refluxed in 178 parts of tetrahydrofuranfor 5 min and filtered off again. The combined filtrates were evaporatedand the residual oil crystallized on standing, yielding 18.4 parts(100%) of (S)-7-chloro2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepine(interm. 59).

b) To a cooled (0° C.) solution of 3.92 parts of intermediate 59 and2.03 parts of N,N-diethylethanamine in 53.2 parts of dichloromethanethere was added dropwise a solution of 2.1 parts of cyclopropylcarbonylchloride in 26.6 parts of dichloromethane under argon. The mixture wasleft at room temperature for 24 hours and was then filtered. Thefiltrate was washed with NaHCO₃ (sat.), dried, filtered and evaporated,yielding 2.88 parts (54.4%) of(S)-7-chloro-4-(cyclopropylcarbonyl)-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepine(interm. 60).

c) To a cooled (0° C.) amount of 7.6 parts of conc. nitric acid therewere added portion-wise 1.59 parts of intermediate 60 under argon. Aftercooling at 0° C. for ½ hour, the reaction mixture was slowly added to 50parts of ice-water while stirring. The precipitate was filtered off,rinsed with 50 parts of ice-water and dried, yielding 1.91 parts (98.5%)of(S)-7-chloro-4-(cyclopropylcarbonyl)-2,3,4,5-tetrahydro-3-methyl-9-nitro1H-1,4-benzodiazepine (interm. 61).

d) To a cooled (0° C.) suspension of 1.37 parts of lithium aluminumhydride in 30.5 parts of 1,2-dimethoxyethane there were addedportionwise 1.79 parts of intermediate 61 under argon. The mixture wasleft at room temperature for ½ hour and was then refluxed for 15 hours.After cooling to 0° C., there were added successively a mixture of 1.4parts of water and 3.7 parts of tetrahydrofuran, 1.6 parts of NaOH 15%and 4.2 parts of water. The whole was stirred for 1 hour and thenfiltered. The precipitate was refluxed in 31 parts of tetrahydrofuranfor 5 min and filtered off again. The combined filtrates were evaporatedand the residual oil was used without further purification, yielding(S)-7-chloro-4-(cyclopropylmethyl)-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 62).

Example 12

a) To a cooled (0° C.) mixture of 18.9 parts of(S)-N-[(1,1,-dimethylethoxy)carbonyl]-alanine, 10.8 parts of2-methyl-2-propen-1-amine monohydrochloride, 27.0 parts of1-hydroxy-1H-benzotriazle hydrate and tetaahydrofuran, there were added10.1 parts of N-methylmorpholine and, after 20 min, 20.6 parts ofN,N-methanetetraylbis-[cyclohexanamine] under a nitrogen atmosphere. Thewhole was kept at 0° C. for 1 hour and at room temperature for 12 hours.The solvent was evaporated and the residue was partitioned betweendichloromethane and NaHCO₃ (sat.). The organic layer was separated,washed with NaCl (sat), dried, filtered and evaporated, yielding 24.2parts (99.9%) of (1,1-dimethylethyl)(S)-[1-methyl-2-[(2-methyl-2-propenyl)amino]-2-oxoethyl]carbamate(interm. 63).

b) To a cooled (0° C.) amount of 88.8 parts of trifluoroacetic acidthere were slowly added 14.3 parts of intermediate 63. The mixture waskept at 0° C. for 3 hours and was then evaporated. The residual oil wasextracted with NaHCO₃ (sat.) and the aqueous layer was continuouslyextracted with dichloromethane overnight. The extract was dried,filtered and evaporated, yielding 4.2 parts (49.2%) of(S)-2-amino-N-(2-methyl-2-propenyl)propanamide (interm. 64).

c) To a solution of 3.2 parts of lithium aluminum hydride in 22.3 partsof tetrahydrofuran there was slowly added a solution of 4.2 parts ofintermediate 64 in 22.3 parts of tetrahydrofuran under argon. Afterrefluxing for 16 hours and subsequent cooling to 0° C., there were addedsuccessively 3.2 parts of water, 9.6 ml of NaOH (3N) and 3.2 parts ofwater. The whole was filtered and the solid was washed with 22.3 partsof tetrahydrofuran. The combined filtrates were dried, filtered andevaporated, yielding 2.0 parts (46.8%) of(S)-N¹-(2-methyl-2-propenyl)-1,2-propanediamine (interm. 65).

d) A mixture of 5.0 parts of 2,5-dichloro-3-nitrobenzoic acid and 16.2parts of thionyl chloride was refluxed for 24 hours under argon. Thereaction mixture was evaporated, yielding 4.74 parts (87.5%) of2,5-dichloro-3-nitrobenzoyl chloride (interm. 66).

e) A mixture of 4.0 parts of intermediate 66; 40.5 parts of 1-butanoland 5.4 parts of sodium carbonate was refluxed for 2 hours under argon.There were added 2.0 parts of intermediate 65 and refluxing wascontinued for 16 hours. The reaction mixture was filtered and thefiltrate was evaporated. The residue was purified by flash columnchromatography (silica gel; CH₂Cl₂/CH₃OH 99:1). The eluent of thedesired fraction was evaporated, yielding 1.43 parts (27.2%) of(+)-(S)-7-chloro-1,2,3,4-tetrahydro-2-methyl-4-(2-methyl-2-propenyl)-9-nitro-5H-1,4-benzodiazepin-5-one;mp. 66.5° C.; [α]_(D) ²⁵ =+314.5° (conc.=0.325% in CH₃OH) (interm. 67).

In a similar manner there was also prepared:

(−)-(R)-7-chloro-4-(cyclopropylmethyl)-1,2,3,4-tetrahydro-2-methyl-9-nitro-5H-1,4-benzodiazepin-5-one;mp. 79.7° C.; [α]_(D) ²⁵=314.5° (conc.=0.73% in CH₃OH) (interm. 68).

Example 13

a) To a homogeneous solution of 8.42 parts of (S)-2-aminopropanamidemonohydrobromide, 12.26 parts of sodium acetate and 79 parts of methanolthere were added 10.96 parts of 2,6-dichloro-3-nitrobenzaldehyde and,after ½ hour, a mixture of 3.77 parts of sodium cyanotrihydroborate and7.9 parts of methanol. The whole was stirred for 45 min at roomtemperature. After acidifying to pH 1 with HCl (3N), stirring wascontinued overnight. The reaction mixture was evaporated and the residuewas basified with NaHCO₃ (sat). The product was extracted withdichloromethane and the extract was dried, filtered and evaporated. Theresidue was recrystallized from 2-propanol yielding 10.29 parts (70.7%)of (S)-2-[[(2,6-dichloro-3-nitrophenyl)methyl]amino]propanamide (interm.69).

b) A mixture of 10.03 parts of intermediate 69; 348 parts of1,2-dimethoxyethane and 92.5 parts of a solution of boranetetrahydrofurancomplex in tetrahydrofuran 1M was stirred for 3 days atroom temperature under argon. There were slowly added 142 parts ofmethanol and 180 ml of HCl (3N) and stirring was continued over weekend.The reaction mixture was basified with 200 ml of NaOH (3N) and was thenevaporated. The residue was extracted with dichloromethane and theextract was dried, filtered and evaporated. The residue was refluxed ina mixture of 3.0 parts of sodium acetate and 81 parts of 1-butanol for 3days under argon. The solvent was evaporated and the residue wasdissolved in dichloromethane. This solution was washed with NaHCO₃,dried, filtered and evaporated. The residue was purified twice by flashcolumn chromatography (silica gel; CH₂Cl₂/CH₃OH 99:1). The eluent of thedesired fraction was evaporated and the residue was converted into the(E)-2-butenedioate salt in methanol. The salt was filtered off (1stfraction) and the mother liquor was evaporated. The residue waschromatographed and also converted into the salt (2nd fraction). Thecombined fractions were treated with a mixture of dichloromethane andNaOH (3N) to set free the base, yielding 3.73 (45.0%) of(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine(interm. 70).

c) A mixture of 1.80 parts of intermediate 70; 1.21 parts of sodiumcarbonate, 1.24 parts of potassium iodide, 9.4 parts ofN,N-dimethylformamide and a solution of 1.37 parts of1-bromo-3-methyl-2-butene in 7.5 parts of N,N-dimethylformamide wasstirred overnight at room temperature. The reaction mixture wasextracted with dichloromethane and the extract was dried, filtered andevaporated. The residue was purified by flash column chromatography(silica gel; CH₂Cl₂/CH₃OH 98:2). The eluent of the desired fraction wasevaporated, yielding 1.93 parts (83.6%) of(S)-6chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine(interm. 71).

d) To a cooled (0° C.) mixture of 0.90 parts of lithium aluminum hydrideand 22.3 parts of tetrahydrofuran there was added dropwise a solution of1.84 parts of intermediate 71 and 22.3 parts of tetrahydrofuran underargon. The whole was stirred for 1 hour at 0° C., for 1½ hours at roomtemperature and for 8 hours at reflux temperature. After cooling to 0°C., there were added successively a mixture of 0.9 parts of water and44.5 parts of tetrahydrofuran, 0.9 ml of NaOH (3N) and 2.7 parts ofwater. The mixture was filtered over diatomaceous earth and theprecipitate was washed with hot tetrahydrofuran. The combined filtrateswere evaporated, yielding 1.75 parts (100%) of(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine (interm. 72).

In a similar manner there were also prepared:

(S)-6-chloro-4-(3-ethyl-2-pentenyl)-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9amine(interm. 73); and

6-chloro-2,3,4,5-tetrahydro-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine (interm. 74).

Example 14

a) To a cooled (0° C.) suspension of 2.0 parts of lithium aluminumhydride in 51.5 parts of 1,4-dioxane there was added a solution of 2.1parts ofcis-1,2,3,4-tetrahydro-2,3-dimethyl-9-nitro-5H-1,4-benzodiazepin-5-one(prepared as intermediate 4) in 36.1 parts of 1,4-dioxane. The whole wasrefluxed overnight. After cooling, there were added successively 2 partsof water, 6 ml of NaOH (3N) and 2 parts of water. The mixture wasfiltered and the filtrate was evaporated, yielding 1.67 parts (97.8%) of(2,3-cis)-2,3,4,5-tetrahydro-2,3-dimethyl-1H-1,4-benzodiazepin-9-amine(interm. 75).

b) To a cooled (0° C.) solution of 1.66 parts of trichloromethylchloroformate in 39.9 parts of dichloromethane there was added dropwisea solution of 1.60 parts of intermediate 75 and 2.54 parts ofN-methylmorpholine in 66.5 parts of dichloromethane. The whole wasstirred over weekend at room temperature and was then evaporated. Theresidue was heated on a steam-bath for 2 hours in 50 ml of a mixture of1,4-dioxane and water (15:85). After cooling, the mixture wasneutralized with NH₄OH (conc.) and extracted with dichloromethane. Theextract was washed with NaCl (sat.), dried, filtered and evaporated. Theresidue was purified by flash column chromatography (silica gel;CH₂Cl₂/CH₃OH/NH₄OH 93:7:0.1). The eluent of the desired fraction wasevaporated, yielding 0.8 parts (43.9%) of(4,5-cis)-4,5,6,7-tetrahydro-4,5-dimethylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one(interm. 76).

Example 15

a) A mixture of 298.42 parts of(S)-7-chloro-3,4-dihydro-3-methyl-9-nitro-1H-1,4-benzodiazepine-2,5-dione(prepared as interm. 44) and 3324 parts of ethanol was hydrogenated at50° C. and normal pressure with 21.04 parts of platinum-on-charcoalcatalyst 5%. At the end of the hydrogenation, the temperature was raisedto 70° C. The reaction mixture was filtered while hot and the catalystwas washed with boiling ethanol. The filtrate was stirred overnight inan ice-bath and was then concentrated. The residue was cooled on ice.The precipitate was filtered off, washed with methylbenzene and dried invacuo at 50° C., yielding 187.7 parts (74.6%) of(S)-9-amino-7-chloro-3,4-dihydro-3-methyl-1H-1,4-benzodiazepine-2,5-dione(interm. 77).

b) To a cooled (ice-bath) suspension of 29.3 parts of lithium aluminumhydride in 392 parts of 1,2-dimethoxyethane there were added portionwise30.78 parts of intermediate 77 under a nitrogen atmosphere. The wholewas refluxed for 22 hours and subsequently cooled to 0-50° C. There wereadded successively a mixture of 36.5 parts of 1,2-dimethoxyethane and 42parts of water, 48.7 parts of NaOH (15%) and 135 parts of water. Afterstirring for 15 min, the mixture was filtered and the precipitate waswashed with 1,2-dimethoxyethane. The combined filtrates were evaporatedand the residue was dried, yielding 25.4 parts (93.7%) of(S)-7-chloro-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 78).

c) To a heated (40° C.) solution of 91 parts of intermediate 78 in 500ml of 1,2-dimethoxyethane there were added successively 1253 parts ofN,N-dimethylformamide, 66.98 parts of sodium carbonate and 71.38 partsof potassium iodide. After cooling to 0-5° C., there was added dropwisea solution of 271.3 parts of 1-chloro-3-methyl-2-butene in 270 parts ofN,N-dimethylformamide under a nitrogen atmosphere. The whole was stirredfor 18 hours at 0-5° C. and was then partitioned between dichloromethaneand water. The aqueous layer was separated and re-extracted withdichloromethane. The combined dichloromethane layers were washed withwater (7×), dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; C₆H₅CH₃/i.C₃H₇OH 98.2). The eluent ofthe desired fraction was evaporated, yielding 43.64 parts (51.8%) of(S)-7-chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 79).

Example 16

A suspension of 1.0 part of compound 19 in 8.25 parts of phosphorylchloride was heated for 15 hours at 90° C. under a nitrogen atmosphere.The reaction mixture was evaporated and the residue was partitionedbetween NaHCO₃ (sat.) and dichloromethane. The aqueous layer wasre-extracted with dichloromethane. The combined organic layers werewashed with NaHCO₃ (sal) and NaCl (sal), dried, filtered and evaporated,yielding 1.05 parts (98.3%) of2-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine(interm. 80).

In a similar manner there was also prepared:

(−)-(S)-2,9-dichloro-6-(cyclopentylmethyl)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepine (interm. 81).

Example 17

A suspension of 38.16 parts of compound 27 and 15 parts of sodiumcarbonate in 578 parts of phosphoryl chloride was stirred for 2 days at60° C. under a nitrogen atmosphere. The excess of phosphoryl chloridewas distilled off under vacuum at 30-50° C. After cooling on ice, theresidue was dissolved in 500 parts of water. This solution was carefullybasified with 1000 ml of NaHCO₃ (sal). The product was extracted withdichloromethane (3×355 parts) and the combined extracts were washed withNaHCO₃ (sat.) and NaCl (sal), dried, filtered and evaporated, yielding27 parts (66.5%) of(S)-2-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine(interm. 82).

In a similar manner there were also prepared the intermediates listed inTable 2 hereinbelow.

TABLE 2

Rnr Int. No. R¹ R² R⁴ Physical data 82.912 83 —CH₂—CH═C(CH₃)₂ CH₃ 9-Cl(S) 83.157 84 —CH₂—CH═C(CH₃)₂ CH₃ H (R) 84.673 85 —CH₂—CH═C(CH₃)₂ CH₃8-CH₃ (S) 84.965 86 —CH₂—CH═C(CH₃)₂ CH₃ 9-Cl (R) 85.149 87—CH₂—CH═C(CH₃)₂ H 9-Cl — 85.172 88 —CH₂—CH═C(CH₃)₂ CH₃ 9-F (S) 85.786 89

CH₃ 9-Cl (S) 86.084 90

CH₃ 9-Cl (S) 86.161 91 —CH₂—CH═C(C₂H₅)₂ CH₃ 9-Cl (S) 86.177 92—CH₂—CH═C(CH₃)₂ CH₃ 9-CF₃ (S)

Example 18

To a cooled (−78° C.) solution of 1.23 parts of compound 114 in 93.1parts of dichloromethane under argon, there were added successively 1.38parts of trifluoroacetic anhydride, after 10 min, 0.79 parts of2,6-dimethylpyridine and, after 15 min, 23 ml of a solution of HCl in1,1′-oxybisethane (0.8N). The whole was left for 15 min and was thenpoured into NaHCO₃ (sat.). The organic layer was separated, dried,filtered and evaporated, yielding 1.61 parts (100%) of(S)-2,8-dichloro-6-(3-ethyl-2-pentenyl)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepine(interm. 93).

In a similar manner there were also prepared:

(4,5-cis)-2-chloro-4,5,6,7-tetrahydro-4,5-dimethyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine(interm. 94); and

(S)-2,9-dichloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methylbutyl)imidazo[4,5,1-jk][1,4]benzodiazepine (interm. 95).

Example 19

A mixture of 8 parts of compound 3 in 80 parts of acetic acid washydrogenated at normal pressure and 38° C. with 1 part ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was taken up in 75 parts of water and thewhole was basified with 30 parts of concentrated ammonium hydroxide. Themixture was left to crystallize at room temperature. The product wasfiltered off and recrystallized from 2-propanol, yielding 3.7 parts(66.8%) of 4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-one; mp. 190.5° C. (interm. 96).

In a similar manner there was also prepared:

4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one; mp.208-220° C. (interm. 97).

Example 20

a) To a mixture of 7.76 parts of intermediate 4 and 445 parts oftetrahydrofuran there were added 104 parts of a solution of boranetetrahydrofuran complex in tetrahydrofuran 1M. After refluxing for 4days, there were added 50 parts of water and 150 ml of NaOH (3N).Refluxing was continued for 3 hours. The organic layer was separated,washed with NaCl (sat.) (2×), dried, filtered and evaporated. Theresidue was purified by flash column chromatography (silica gel;CH₂Cl₂/CH₃OH/NH₄OH 93:7:0.1). The eluent of the desired fraction wasevaporated, yielding 0.51 parts (8.1%) of(2,3-trans)-2,3,4,5-tetrahydro-2,3-dimethyl-1H-1,4-benzodiazepin-9-amine(interm. 98).

b) A mixture of 0.51 parts of intermediate 98; 0.52 parts of1,1′-thiocarbonylbis[1H -imidazole] and 17.8 parts of tetrahydrofuranwas refluxed for 4 hours. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was separated, washed withwater (2×) and NaCl (sal), dried, filtered and evaporated, yielding 0.38parts (61.0%) of(4,5-trans)-4,5,6,7-tetrahydro4,5-dimethylimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione(interm. 99).

B. Preparation of the final compounds Example 21

To a solution of 0.93 parts of intermediate 14; 3.95 parts of ethanoland 1 part of water there were added 0.32 parts of potassium hydroxideand, after 8 min, 0.43 parts of carbon disulfide. The mixture wasstirred for 10 min at room temperature and heated for 1 hour at 90° C.After cooling to room temperature, there were added 5.6 parts of waterand 0.49 parts of acetic acid. The solid was filtered off andpartitioned between diluted ammonium hydroxide and dichloromethane. Theorganic layer was dried, filtered and evaporated. The residue wastriturated in acetonitrile and recrystallized from ethanol, yielding0.28 parts (25.2%) of4,5,6,7-tetrahydro-7-methyl-6-propylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione;mp. 179.1° C. (comp. 41).

Example 22

A mixture of 2.8 parts of intermediate 12; 2.55 parts of1,1,′-carbonothioylbis[1H-imidazole] and 44.5 parts of tetrahydrofuranwas refluxed on a steam bath for ½ hour under an argon atmosphere. Thereaction mixture was evaporated and the residue was partitioned betweendichloromethane and water. The organic layer was separated, dried,filtered and evaporated. The residue was purified by flash columnchromatography (silica gel; CH₂Cl₂/CH₃OH 99:1). The eluent of thedesired fraction was evaporated and the residue was crystallized fromethanol. The product was filtered off and dried, yielding 1.08 parts(33.2%) ofcis-4,5,6,7-tetrahydro-5,7-dimethyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)thione;mp. 138.3° C. (comp. 52).

Example 23

A mixture of 0.216 parts of intermediate 99; 0.07 parts ofcyclopropanecarboxaldehyde, 0.116 parts of sodium cyanotrihydroborate,55.7 parts of acetic acid, 7.9 parts of methanol and 4.5 parts oftetrahydrofuran was stirred for 2 days at room temperature. The reactionmixture was acidified with HCl and stirring was continued until gasevolution ceased. The whole was neutralized with NaOH (3N) and filtered.The filtrate was evaporated and the residue was partitioned between NaOH(1N) and dichloromethane. The organic layer was dried, filtered andevaporated. The residue was purified by flash column chromatography(silica gel; CH₂Cl₂/CH₃OH/NH₄OH 95:5:0.1). The eluent of the desiredfraction was evaporated and the residue was crystallized from1,1′-oxybisethane. The product was filtered off and dried in vacuo atroom temperature overnight, yielding 0.13 parts (49.1%) of(4,5-trans)-6-(cyclopropylmethyl)-4,5,6,7tetrahydro-4,5-dimethylimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;mp. 135.2° C. (comp. 57).

Example 24

A solution of 0.71 parts of intermediate 19; 0.45 parts of1,1′-carbonylbis[1H-imidazole] and 22.3 parts of tetrahydrofuran wasstirred for 1½ hour at reflux temperature and overnight at roomtemperature. The reaction mixture was evaporated and the residue wasdissolved in ethyl acetate. This solution was washed successively withwater (2×), diluted acetic acid, water (2×) and NaCl (sat.) and was thendried, filtered and evaporated. The residue was purified by flash columnchromatography (silica gel; hexane/CH₃COOC₂H₅ 3:1). The eluent of thedesired fraction was evaporated and the residue was crystallized fromacetonitrile. The product was filtered off and dried, yielding 0.36parts (47.1%) of9-chloro-4,5,6,7-tetrahydro-7-methyl-6(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 138.7° C. (comp. 82).

Example 25

A mixture of 19.8 parts of intermediate 23 and 7.2 parts of urea washeated at 210-220° C. until foaming and NH₃ evolution ceased (about 10min). After cooling to 100° C., there were added 120 parts of HCl (1 N).The solution was decanted from the oily residue, boiled with activatedcharcoal and filtered. After cooling, the filtrate was basified withammonium hydroxide and extracted with trichloromethane (75 and 150parts). The combined extracts were dried, filtered and evaporated. Theresidue was triturated in 2-propanol and was then crystallized fromethanol and from 4-methyl-2-pentanone. The product was filtered off anddried, yielding 2.5 parts (11.5%) of4,5,6,7-tetrahydro-5-methyl-6-(phenylmethyl)-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one;mp. 205° C. (comp. 3).

Example 26

To a cooled (0° C.) mixture of 0.93 parts of intermediate 14; 0.86 partsof 4-methylmorpholine and 40 parts of dichloromethane there was addeddropwise a solution of 0.43 parts of trichloromethyl chloroformate in 20parts of dichloromethane under argon. After stirring for ½ hour at 0°C., the product was extracted with a sodium hydrogen carbonate solution.The extract was dried, filtered and evaporated. The residue was purifiedby flash column chromatography (silica gel; CH₂Cl₂/CH₃OH 15:1). Theeluent of the desired fraction was evaporated and the residue wastriturated with acetonitrile, yielding 0.32 parts (61.5%) of4,5,6,7-tetrahydro-7-methyl-6-propyl-imidazo[4,5,1-jk)][1,4]benzodiazepin-2(1H)-one(comp. 40); mp. 124.0° C.

Example 27

A mixture of 43.0 parts of intermediate 79; 3152 parts ofdichloromethane and 30.1 parts of N,N-diethylethanamine was stirred at0-5° C. under a nitrogen atmosphere and screened from light. There wasadded dropwise a solution of 16.3 parts of thiophosgene in 299 parts ofdichloromethane at 0-5° C. The whole was stirred for 1 hour at 0-5° C.and was then concentrated to about 1000 ml. The residue was washed withwater (2×), dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; C₆H₅CH₃/CH₃COOC₂H₅ 88:12). The eluentof the desired fraction was evaporated, yielding 19.5 parts (51.2%) of(+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H-thione;mp. 186.3° C.; [α]_(D) ²⁰=+11.8° (conc.=1% in CH₃OH) (comp. 38).

Example 28

To a suspension of 1.14 parts of lithium aluminium hydride in 21.8 partsof 1,2-dimethoxyethane there was added a solution of 1.28 parts ofintermediate 67 in 21.8 parts of 1,2-dimethoxyethane under argon. Afterrefluxing for 14 hours and subsequent cooling, there were addedsuccessively 1.1 parts of water, 3.4 ml of NaOH (3N) and 1.1 parts ofwater. The whole was stirred for 15 min and was then filtered. Theprecipitate was washed with dichloromethane and the combined filtrateswere dried, filtered and evaporated. The residue was dissolved in 17.8parts of tetrahydrofuran. There were added 0.9 parts of1,1′-thiocarbonylbis[1H-imidazole] and the whole was refluxed for 3hours. The product was extracted with ethyl acetate (9.0 parts) and theextract was washed with water (3×25 parts), dried, filtered andevaporated. The residue was purified by flash column chromatography(silica gel; CH₂Cl₂/C₂H₅OH 99:1). The eluent of the desired fraction wasevaporated and the residue was crystallized from acetonitrile. Theproduct was filtered off and dried, yielding 0.20 parts (12.9%) of(+)-(S)-9-chloro-4,5,6,7-tetraydro-4-methyl-6-(2-methyl-2-propenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;mp. 171.4° C.; [α]_(D) ²⁵=+20.5° (conc.=0.77% in CH₃OH) (comp. 79).

Example 29

To a mixture of 6.84 parts of lithium aluminum hydride and 90 parts oftetrahydrofuran there was added a solution of 9 parts of intermediate 2in 90 parts of tetrahydrofuran. After stirring for 2½ hour, there wereadded successively water and NaOH 15% while cooling on ice. The wholewas filtered and the filtrate was evaporated. The residue was taken upin methylbenzene and this solution was dried, filtered and evaporated.The residue was heated at 200° C. for 10 min with 2 parts of urea. At100° C., the whole was diluted with 25 parts of boiling water. Theaqueous layer was decanted and the residue was treated with activatedcharcoal in a mixture of 35 parts of HCl (1N) and 35 parts of water.After filtration, the mixture was basified with NH₄OH and the productwas extracted with methylbenzene (80 parts and 40 parts). The combinedextracts were dried, filtered and evaporated. The residue wascrystallized from 4-methyl-2-pentanone and then converted into themonohydrochloride salt in methanol by addition of 2-propanol saturatedwith HCl. The salt was filtered off, recrystallized from water anddried, yielding 3.2 parts of6-(phenylmethyl)-4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-onemonohydrochloride; mp. 258.5-262° C. (comp. 1).

Example 30

A mixture of 0.6 parts of compound 45 and 16.5 parts of phosphorylchloride was refluxed for 45 min under argon. Gaseous HCl was bubbledthrough the refluxing mixture for 2 hours. The solvent was evaporatedand the residue was diluted with 10 parts of water. After neutralizingwith NaHCO₃ (sat.), the product was extracted with dichloromethane. Theextract was dried, filtered and evaporated and the residue was dissolvedin 7.9 parts of ethanol. There was added 1.0 part of thiourea and thewhole was refluxed for 3 hours and then evaporated. The residue waspartitioned between dichloromethane and water. The organic layer wasseparated, dried, filtered and evaporated. The residue was purified byflash column chromatography (silica gel; CH₂Cl₂/C₂H₅OH 95:5). The eluentof the desired fraction was evaporated and the residue was dried invacuo at 78° C. overnight, yielding 0.20 parts (31.8%) of(+)-(S)-6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;mp. 197.4° C.; [α]_(D) ²⁵=+21.4° (conc.=0.83% in CHCl₃) (comp. 48).

Example 31

To a mixture of 0.562 parts of compound 63 and 0.262 parts of sodiumcarbonate there were added 9.245 parts of phosphoryl chloride under anargon atmosphere. After stirring for 23 hours at 95° C., the reactionmixture was evaporated. The residue was partitioned betweendichloromethane and NaHCO₃ (sat.). The organic layer was separated,washed with NaHCO₃ (sat.) and NaCl (sat.), dried, filtered andevaporated. The residue was mixed with 0.517 parts of thiourea and 7.9parts of ethanol under argon. After stirring for 22 hours at 95° C., thewhole was evaporated and the residue was partitioned again betweendichloromethane and NaHCO₃ (sat). The organic layer was washed withNaHCO3 (sat) and NaCl (sat), filtered over diatomaceous earth andevaporated. The residue was purified by flash column chromatography(silica gel; CH₃COOC₂H₅/hexane 10:90→40:60). The eluent of the desiredfraction was evaporated and the residue was crystallized from ethylacetate. The product was filtered off and dried in vacuo at 82° C. for 6hours, yielding 0.21 parts (35.7%) of(S)-9,10dichloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;mp. 172.8° C. (comp. 64).

Example 32

To a cooled (−78° C.) solution of 1.18 parts of compound 99 in 100 partsof dichloromethane under argon, there were added successively and with15 minutes-intervals 1.26 parts of trifluoroacetic anhydride, 0.61 partsof 2,6-dimethylpyridine and 21.1 ml of 1,1′-oxybisethane, saturated withHCl. The whole was stirred for ½ hour and was then neutralized withNaHCO₃ (sat.). The product was extracted with dichloromethane (2×66.5parts) and the extract was dried, filtered and evaporated. The residuewas purified by flash column chromatography (silica gel;CH₂Cl₂/CH₃OH/NH₄OH 98:2:01). The eluent of the desired fraction wasevaporated and the residue was dissolved in 7.9 parts of ethanol. Therewere added 2.0 parts of thiourea and the whole was refluxed for 6 hoursand then evaporated. The residue was partitioned between water anddichloromethane. The organic layer was separated, washed with NaHCO₃(sat.) and NaCl (sat.), dried, filtered and evaporated. The residue waspurified by flash column chromatography (silica gel; hexane/CH₃COOC₂H₅75:25). The eluent of the desired fraction was evaporated and theresidue was crystallized from acetonitrile. The product was filtered offand dried in vacuo at 60° C., yielding 0.284 parts (20.2%) of(+)-(S)-8-bromo-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;mp. 161.1° C.; [α]_(D) ²⁵=+4.6° (conc.=1% in CH₃OH) (comp. 100).

Example 33

To a stirred solution of 1.0 part of intermediate 80 in 39.5 parts ofethanol there were added 0.5 parts of thiourea. Stirring was continuedfor 20 hours at room temperature under a nitrogen atmosphere and for 3hours at reflux temperature. The reaction mixture was evaporated and theresidue was partitioned between water and dichloromethane. The organiclayer was dried, filtered and evaporated, yielding an oily residue. Theaqueous layer was basified with NaHCO₃ (aq.) and extracted withdichloromethane (3×). The combined extracts were washed with NaCl(sat.), dried, filtered and evaporated, yielding a similar oily residue.The combined oils were purified by flash column chromatography (silicagel; CH₃COOC₂H₅/hexane 25:75). The eluent of the desired fraction wasevaporated and the residue was dried in an Abderhalen (i.C₃H₇OH refluxfor 3 hours and at room temperature overnight), yielding 0.41 parts(40.7%) of(+)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione;mp. 128.0° C. (comp. 31).

Example 34

To a mixture of 1.00 part of intermediate 96; 0.782 parts of sodiumcarbonate, 0.816 parts of potassium iodide and 94 parts ofN,N-dimethylformamide there were added 1.18 parts of 2,3-dibromopropeneunder an argon atmosphere. The whole was heated at 65-70° C. for 5 hoursunder argon and was then evaporated. The residue was partitioned betweendichloromethane and water. The organic layer was separated and washedwith water. The combined aqueous layers were re-extracted withdichloromethane. The combined organic layers were washed with NaCl(sat.), dried, filtered and evaporated. The residue was dissolved inrefluxing acetonitrile and recrystallized upon cooling (2×). The productwas filtered off, washed with cold acetonitrile and dried in vacuo at82° C., yielding 0.762 parts (48.1%) of6-(2-bromo-2-propenyl)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 150.0° C. (comp. 20).

Example 35

To a cooled (0° C.) amount of 2.96 parts of trifluoroacetic acid therewere added 2.0 parts of intermediate 32 under argon. After stirring for2 hours at 0° C., the mixture was evaporated. To the residue there wereadded successively 18.8 parts of N,N-dimethylformamide, 0.86 parts of1-bromo-3-methyl-2-butene, 3.0 parts of sodium carbonate and 0.96 partsof potassium iodide. The whole was stirred overnight at room temperatureand was then evaporated. The residue was partitioned between water andethyl acetate. The organic layer was separated, washed with NaHCO₃ (sal)and NaCl (sat.), dried, filtered and evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and driedin vacuo at 60° C. overnight, yielding 1.5 parts (81.7%) of(+)-(S)-8-bromo-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one;mp. 125.2° C.; [α]_(D) ²⁵=+12.6° (conc.=1% in CH₃OH) (comp. 99).

Example 36

To a stirred mixture of 0.59 parts of intermediate 47; 0.39 parts ofsodium carbonate and 4.7 parts of N,N-dimethylformamide were added 0.28parts of 3-chloro-2-methyl-1-propene under an argon atmosphere. Afterstirring for 4 days at room temperature, the solvent was evaporated andthe residue was taken up in NaCl (sat). The product was extracted withdichloromethane (3×) and the combined extracts were washed with NaCl(sat.), dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CH₂Cl₂/CH₃OH 10:1). The eluent of thedesired fraction was evaporated and the residue was triturated withacetonitrile, yielding 0.18 parts (24.7%) of9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(2-methyl-2-propenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H-one;mp. 174.9° C. (comp. 35).

Example 37

A mixture of 6.1 parts of intermediate 96; 6.7 parts of2-bromoethylbenzene, 3.6 parts of N,N-diethylethanamine, a few crystalsof potassium iodide and 80 parts of 1-butanol was stirred for 24 hoursat reflux temperature. The reaction mixture was evaporated and theresidue was diluted with 100 parts of water. The product was extractedwith trichloromethane (2×75 parts) and the combine extracts were dried,filtered and evaporated. The residue was successively crystallized from4methyl-2-pentanone (2×) and from methanol. The product was filtered offand dried, yielding 3.4 parts of4,5,6,7-tetrahydro-5-methyl-6-phenylethylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 150° C. (comp. 4).

Example 38

To a stirred and cooled (−60 to −50° C.) amount of 45.3 parts ofconcentrated nitric acid there were added portionwise 2.75 parts ofcompound 45 under an argon atmosphere. When a clear solution wasobtained, stirring and cooling was continued for ½ hour. The reactionmixture was slowly poured into 400 parts of ice-water and the whole wasbasified to pH 8 with Na₂CO₃. The precipitated product was filtered offand dried in vacuo at 50° C. for 16 hours, yielding 0.5 parts (15.6%) ofa mixture of(S)-6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-5-methyl-9-nitroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-oneand the 8-nitro-isomer thereof (75:25) (comp.67).

Example 39

To a refluxing mixture of 1.03 parts of hydrazine monohydrate, 23.7parts of methanol and 0.015 parts of Raney nickel there were addedportionwise 0.5 parts of compound 67. After refluxing for 20 min andsubsequent cooling, the reaction mixture was filtered over diatomaceousearth and the filtrate was evaporated. The residue was purified bypreparative thin layer chromatography (eluens: CH₂Cl₂/CH₃OH 90:10). Theeluent of the pure fractions was evaporated and the residue was dried invacuo at 50° C. for 16 hours, yielding 0.17 parts (39.0%) of(+)-(S)-9-amino6-(cyclopropyl-methyl)-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one;mp. 188.7° C.; [α]_(D) ²⁵=+13.4° (conc.=0.50% in trichmoromethane)(comp. 68).

Example 40

To a stirred solution of 0.32 parts of compound 68 in 26.7 parts oftetrahydrofuran there were added 0.093 parts of acetyl chloride.Stirring was continued for 16 hours at room temperature. The reactionmixture was evaporated and the residue was basified with Na₂CO₃ (sat.).The product was extracted with trichloromethane and the extract wasdried, filtered and evaporated. The residue was purified by flash columnchromatography (silica gel; CH₂Cl₂/CH₃OH 100:0→97:3). The eluent of thedesired fraction was evaporated and the residue was dried in vacuo at50° C. for 16 hours, yielding 0.18 parts (47.7%) of(+)-(S)-N-[6-(cyclopropylmethyl)-1,2,4,5,6,7-hexahydro-5-methyl-2oxoimidazo[4,5,1-jk][1,4]benzodiazepin-9-yl]acetamide;mp. 243.9° C.; [α]_(D) ²⁵=+15.1° (conc.=0.43% in methanol) (comp. 81).

All the other compounds listed in Table 3 were obtained by analogousmethods of preparation as described in Ex. 21-40, the actual method ofpreparation being indicated in column 2 (Ex. No.).

TABLE 3

Co. Ex. No. No. X R¹ R² R³ R⁴ R⁵ R⁶ physical data 1 29 O C₆H₅—CH₂— H H HH H 258.5-262° C. HCl 2 37 O C₆H₅—(CH₂)₂— H H H H H 165.5° C. 3 25 OC₆H₅—CH₂— CH₃ H H H H 205° C. 4 37 O C₆H₅—(CH₂)₂— CH₃ H H H H 150° C. 537 O CH₂═CH—CH₂— CH₃ H H H H 138° C. 6 34 O CH₂═C(CH₃)—CH₂— CH₃ H H H H150.1° C. 7 34 O CH≡C—CH₂— CH₃ H H H H 146.0° C. 8 34 O CH₂═CH—CH₂— CH₃H H H H 113.8° C. (+)-(S) 9 34 O CH₂═CH—(CH₂)₂— CH₃ H H H H 107.2° C. 1034 O C₃H₇— CH₃ H H H H 149.7° C. 11 36 O C₂H₅— CH₃ H H H H 143.2° C./(±)12 34 O CH₂═C(CH₃)—CH₂— CH₃ H H H H 152.4° C. (+)-(S) 13 34 Oc.C₃H₅—CH₂— CH₃ H H H H 97.6° C./H₂O 14 34 O CH₂═C(CH₃)—CH₂— H CH₃ H H H142.1° C. 15 34 O CH₃—CH═CH—CH₂— CH₃ H H H H 127.6° C./(E) 16 34 OCH₃CH═CH—CH₂— CH₃ H H H H 106.0° C./(Z) 17 34 O (CH₃)₂CH—CH₂— CH₃ H H HH 119.7° C. 1/2H₂O 18 34 O C₄H₉— CH₃ H H H H 138.0° C. 19 34 O(CH₃)₂C═CH—CH₂— CH₃ H H H H 158.0° C./(±) 20 34 O CH₂═C(Br)—CH₂— CH₃ H HH H 150.0° C. 21 34 O CH₃CH═C(CH₃)—CH₂— CH₃ H H H H 151.6° C. (+)-(E) 2221 S CH₃—(CH₂)₂— CH₃ H H H H 149-151° C. 23 34 O CH₂═C(CH₃)—CH₂— CH₃ H9-CH₃ H H 154.2° C. 24 34 O C₃H₇— H (CH₃)₂CH— H H H 138.6° C. 25 34 OCH₂═C(CH₃)—CH₂— H (CH₃)₂CH— H H H 142.6° C. 26 34 O (CH₃)₂C═CH—CH— CH₃ HH H H 125.1° C. (−)-(R) 27 34 O (CH₃)₂C═CH—CH— CH₃ H H H H 136.4° C.(+)-(S) 28 34 O C₃H₇— H C₃H₇— H H H 119.0° C. 29 34 O CH₂═C(CH₃)—CH₂— HC₃H₇— H H H 132.2° C. 30 34 O CH₂═C(CH₃)—CH₂— CH₃ H 8-CH₃ H H 170.6° C.31 33 S (CH₃)₂C═CH—CH— CH₃ H H H H 128.0° C./(±) 32 34 O(CH₃)₂C═C(CH₃)—CH₂— CH₃ H H H H 180.6° C. 33 34 O CH₂═C(C₂H₅)—CH₂— CH₃ HH H H 109.1° C. 34 34 O (CH₃)₂CHC(═CH₂)—CH₂— CH₃ H H H H 142.2° C. 35 36O CH₂═C(CH₃)—CH₂— CH₃ H 9-Cl H H 174.9° C. 36 33 S (CH₃)₂C═CH—CH— CH₃ HH H H 174.5° C./(+)-(S) [α]²⁰ _(D 1% EtOH)=+15.9° 37 34 O(CH₃)₂C═CH—CH₂— CH₃ H 9-Cl H H 135.6° C./(+)-(S) [α]²⁰_(D 0.96% MeOH)=+7.7° 38 27 S (CH₃)₂C═CH—CH₂— CH₃ H 9-Cl H H 186.3°C./(+)-(S) [α]²⁰ _(D 1% MeOH)= +11.8° 39 33 S (CH₃)₂C═CH—CH₂— CH₃ H H HH 178.5° C. (−)-(R) [α]²⁵ _(D 0.1% EtOH)=−16.4° 40 26 O C₃H₇— H H H HCH₃ 124.0° C. 41 21 S C₃H₇— H H H H CH 3 179.1° C. 42 34 O(CH₃)₂C═CH—CH₂— CH₃ H 9-Cl H H 134.4° C. (−)-(R) [α]²⁰_(D 0.87% MeOH)=−8.85° 43 21 S (CH₃)₂C═CH—CH₂— H H H H CH₃ 192.4° C. 4426 O (CH₃)₂C═CH—CH₂— H H H H CH₃ 108.8° C. 45 34 O c.C₃H₅—CH₂— CH₃ H H HH 115.9° C. (+)-(S) 46 33 S (CH₃)₂C═CH—CH₂— CH₃ H 9-Cl H H >270° C.(+)-(S)/HCl 47 30 S CH₂═C(CH₃)—CH₂— CH₃ H H H H 137.6° C. (+)-(S) [α]²⁵_(D 1.09% MeOH)=+26.2° 48 30 S c.C₃H₅—CH₂— CH₃ H H H H 197.4° C. (+)-(S)[α]²⁵ _(D 0.83% CHCl) ₃ =+21.4° 49 34 O (CH₃)₂C═CH—CH₂— CH₃ H 8-CH₃ H H189.7° C. (+)-(S) [α]²⁵ _(D 0.88% CHCl) ₃ =+8.8° 50 33 S (CH₃)₂C═CH—CH₂—CH₃ H 8-CH₃ H H 147.6° C. (+)-(S) [α]²⁵ _(D 0.33% MeOH)=+7.4° 51 22 S(CH₃)₂C═CH—CH₂— CH₃ CH₃ H H H 156.0° C./trans 52 22 S (CH₃)₂C═CH—CH₂—CH₃ H H H CH₃ 138.8° C./cis 53 22 S (CH₃)₂C═CH—CH₂— CH₃ H H H CH₃ 138.8°C./trans 54 33 S (CH₃)₂C═CH—CH₂— CH₃ H 9-Cl H H 183.2° C. (−)-(R) [α]²⁵_(D 0.86% MeOH)=−9.2° 55 22 S (CH₃)₂C═CH—CH₂— H CH₃ H H CH₃ 191.4° C.(4,7-trans) 56 22 S (CH₃)₂C═CH—CH₂— H CH₃ H H CH₃ 185.2° C. (4,7-cis) 5723 S c.C₃H₅—CH₂— CH₃ CH₃ H H H 135.2° C. (4,5-trans) 58 34 O(CH₃)₂C═CH—CH₂— H H 9-Cl H H 128-131° C. 59 33 S (CH₃)₂C═CH—CH₂— H H9-Cl H H 226.2° C. 60 21 S c.C₃H₅—CH₂— CH₃ H 9-Cl H H 173.5° C. (+)-(S)[α]²⁵ _(D 1% MeOH)=+12.9° 61 34 O (CH₃)₂C═CH—CH₂— CH₃ H 9-F H H 142-148°C. (+)-(S) [α]²⁵ _(D 1% CHCl3)=+6.6° 62 33 S (CH₃)₂C═CH—CH₂— CH₃ H 9-F HH 174.5° C. (+)-(S) [α]²⁵ _(D 1% CHCl) ₃ =+7.3° 63 36 O (CH₃)₂C═CH—CH₂—CH₃ H 9-Cl 10-Cl H (S)/(Z)** 64 31 S (CH₃)₂C═CH—CH₂— CH₃ H 9-Cl 10-Cl H172.8° C./(S) 65 36 O (C₂H₅)₂C═CH—CH₂— CH₃ H 9-Cl H H 239.4° C.(−)-(S)/HCl [α]²⁵ _(D 1% MeOH)=−7.9° 66 34 O c.C₄H₇—CH₂— CH₃ H 9-Cl H H139.3° C. (−)-(S) [α]²⁵ _(D 0.46% MeOH)=−3.05° 67 38 O c.C₃H₅—CH₂— CH₃ H9-NO₂ H H (S) 68 39 O c.C₃H₅—CH₂— CH₃ H 9-NH₂ H H 188.7° C. (+)-(S)[α]²⁵ _(D 0.5% CHCl) ₃ =+13.4° 69 33 S c.C₄H₇—CH₂— CH₃ H 9-Cl H H 206.8°C. (−)-(S) [α]²⁵ _(D 0.47% CHCl) ₃ =−0.6° 70 36 O Cl—CH═CH—CH₂— CH₃ H9-Cl H H 145.7° C. (−)-[S(E)] [α]²⁵ _(D 0.5% CHCl) ₃ =−17.0° 71 36 OCl—CH═CH—CH₂— CH₃ H 9-Cl H H 141.2° C. (+)-[S(Z)] [α]²⁵ _(D 0.5% CHCl) ₃=+35.6° 72 36 O (C₂H₅)₂C═CH—CH₂— CH₃ H 8-CH₃ H H 117.3° C. (+)-(S) [α]²⁵_(D 1% MeOH)=+4.9° 73 34 O c.C₃H₅—(CH₂)₂— CH₃ H 9-Cl H H 127.7° C.(−)-(S) [α]²⁵ _(D 1% MeOH)=−8.0° 74 34 O (C₂H₅)₂C═CH—CH₂— CH₃ H 9-CH₃ HH 103.0° C./(±) 75 34 O CH₂═CH—(CH₂)₄— CH₃ H 9-Cl H H 127.9° C./(−)-(S)[α]²⁵ _(D 1% MeOH)=−11.0° 76 34 O CH₂═CH—(CH₂)₃— CH₃ H 9-Cl H H 107.5°C./(−)-(S) [α]²⁵ _(D 1% MeOH)=−7.4° 77 33 S c.C₃H₅—(CH₂)₂— CH₃ H 9-Cl HH 174.8° C./(−)-(S) [α]²⁵ _(D 1% MeOH)=−4.7° 78 28 S c.C₃H₅—CH₂— H CH₃9-Cl H H 210.9° C./(−)-(R) [α]²⁵ _(D) =−7.9° c = 0.23% MeOH—CHCl₃(3.6:1) 79 28 S CH₂═C(CH₃)—CH₂— H CH₃ 9-Cl H H 171.4° C./(+)-(S) [α]²⁵_(D 0.77% MeOH)=+20.5° 80 33 S (C₂H₅)₂C═CH—CH₂— CH₃ H 9-Cl H H >280°C./(−)-(S) HCl [α]²⁵ _(D 1% MeOH)=−32.7° 81 40 O c.C₃H₅—CH₂— CH₃ H 9-* HH 243.° C./(+)-(S) [α]²⁵ _(D 0.43% MeOH)=+15.1° 82 24 O (CH₃)₂C═CH—CH₂—H H 9-Cl H CH₃ 138.7° C. 83 22 S (CH₃)₂C═CH—CH₂— H H 9-Cl H CH₃ 197.4°C. 84 34 O (CH₃)₂C═CH—CH₂— CH₃ H 9-CF₃ H H 125.4° C./(S) 85 33 S(CH₃)₂C═CH—CH₂— CH₃ H 9-CF₃ H H 148.3° C./(S) 86 22 S (CH₃)₂C═CH—CH₂—CH₃ H 8-Cl H H 163.3° C./(S) 87 23 O (CH₃)₂CH—(CH₂)₂— CH₃ H 9-Cl H H257.9° C./(−)-(S)/HCl [α]²⁵ _(D 0.1% MeOH)=−2.95° 88 31 S c.C₃H₅—CH₂—CH₃ H 9-NO₂ H H 202.8° C./(+)-(S) [α]²⁵ _(D) =+6.5° (c = 0.17%CHCl₃—MeOH) (3-1) 89 34 O (Cl)₂C═CH—CH₂— CH₃ H 9-Cl H H 151.7°C./(+)-(S) [α]²⁵ _(D 1% MeOH)=+12.8° 90 36 O (C₃H₇)₂C═CH—CH₂— CH₃ H 9-ClH H 200.5° C. (−)-(S)/HCl [α]²⁵ _(D 1% MeOH)=−8.2° 91 39 O c.C₃H₅—CH₂—CH₃ H 8-NH₂ H H 206.0° C./(+)-(S) [α]²⁵ _(D 0.44% MeOH)=+4.5° 92 40 Oc.C₃H₅—CH₂— CH₃ H 8-* H H 227.6° C. (−)-(S) [α]²⁵ _(D 0.44% MeOH)=−1.8°93 36 O

CH₃ H 9-Cl H H 216.6° C. (−)-(S)/HCl [α]²⁵ _(D 1% MeOH)=−7.4° 94 34 O(CH₃)₂C═CH—CH₂— CH₃ CH₃ H H H 151.1° C. (4,5cis) 95 33 S (CH₃)₂C═CH—CH₂—CH₃ CH₃ H H H 162.0° C. (4,5cis) 96 36 O (i.C₃H₇)₂C═CH—CH₂— CH₃ H 9-Cl HH 205.8° C. (−)-(S)/HCl [α]²⁵ _(D 1% MeOH)=−4.0° 97 34 O c.C₅H₉—CH₂— CH₃H 9-Cl H H 186.5° C. (−)-(S) [α]²⁵ _(D 0.78% MeOH)=−8.9° 98 35 O(CH₃)₂C═CH—CH₂— CH₃ H 10-Br H H 163.3° C. (−)-(S) [α]²⁵_(D 0.95% MeOH)=−4.1° 99 35 O (CH₃)₂C═CH—CH₂— CH₃ H 8-Br H H 125.2° C.(+)-(S) [α]²⁵ _(D 1% MeOH)=+12.6° 100 32 S (CH₃)₂C═CH—CH₂— CH₃ H 8-Br HH 161.1° C. (+)-(S) [α]²⁵ _(D 1% MeOH)=+4.6° 101 33 S (CH₃)₂CH—CH₂—CH₂—CH₃ H 9-Cl H H 169.5° C. (−)-(S) [α]²⁵ _(D 0.1% MeOH)=−4.53° 102 34 O(CH₃)₂C═CH—(CH₂)₂— CH₃ H 9-Cl H H 208.8° C./(S)/ HCl [α]²⁵_(D 0.1% MeOH)=0 103 22 S (CH₃)₂C═CH—CH₂— CH₃ H 9-Cl H CH₃ 212.1° C.(+)[5S(5α,7β)] HCl [α]²⁵ _(D 0.1% MeOH)=+57.9° 104 26 O (CH₃)₂C═CH—CH₂—CH₃ H 9-Cl H CH₃ 218.8° C. (+)[5S(5α,7β)] HCl [α]²⁵_(D 0.1% MeOH)=+44.3° 105 33 S c.C₅H₉—CH₂— CH₃ H 9-Cl H H 204.1° C.(−)-(S) [α]²⁵ _(D 0.73% MeOH)=−5.9° 106 26 O (C₂H₅)₂C═CH—CH₂— CH₃ H 8-ClH H 156.8° C. (+)-(S) [α]²⁵ _(D 0.1% MeOH)=+7.15° 107 33 S(C₂H₅)₂C═CH—CH_(2—) CH₃ H 8-Cl H H 113.5° C./(+)-(S) [α]²⁵_(D 0.1% MeOH) =+0.91° 108 22 S (CH₃)₂C═CH—CH₂— H H 8-Cl H H 215.4° C. *CH₃CONH— ** 2-butenedioate

C. Pharmacological Example Example 41

A rapid, sensitive and automated assay procedure [Journal of VirologicalMethods, 20, 309-321 (1988)] was used for the in-vitro evaluation ofanti-HIV agents. An HIV-1 transformed T 4-cell line, MT-4, which waspreviously shown (Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985) tobe highly susceptible to and permissive for HIV infection, served as thetarget cell line. Inhibition of the HIV-induced cytopathic effect wasused as the end point. The viability of both HIV- and mock-infectedcells was assessed spectrophotometrically via the in-situ reduction of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The50% cytotoxic dose (CD₅₀ in μg/ml) was defined as the concentration ofcompound that reduced the absorbance of the mock-infected control sampleby 50%. The percent protection achieved by the compound in HIV-infectedcells was calculated by the following formula:${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\quad {expressed}\quad {in}\quad \%},$

whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the untreated HIV-infected cells;(OD_(C))_(MOCK) is the optical density measured for the untreatedmock-infected cells; all optical density values were determined at 540nm. The dose achieving 50% protection according to the above formula wasdefined as the 50% effective dose (ED₅₀ in μg/ml). The ratio of CD₅₀ toED₅₀ was defined as the selectivity index (SI).

TABLE 4 50% cytotoxic (CD₅₀), 50% effective dose (ED₅₀) and selectivityindex (SI). Comp. CD₅₀ ED₅₀ No. (μg/ml) (μg/ml) SI 31 25 0.013 1923 36325 0.008 40625 38 10 0.005 2000 39 ≧250 0.045 ≧5555 43 177 0.10 1770 4616 0.0066 2424 48 >250 0.0166 >15029 50 22 0.0041 5366 51 14.3 0.038 37053 23 0.0048 4838 54 5.5 0.094 58 59 199 ≦0.028 ≧7107 62 24.7 0.00763250 80 5.2 0.006 850 83 10 0.01 1000 86 15.7 0.001 15700 100 25.40.0011 23090

D. Composition Examples Example 42 Oral Solution

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate aredissolved in 41 of boiling purified water. In 31 of this solution aredissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20g of the A.I. The latter solution is combined with the remaining part ofthe former solution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70%solution are added thereto. 40 g of sodium saccharin are dissolved in0.51 of water and 2 ml of raspberry and 2 ml of gooseberry essence areadded. The latter solution is combined with the former, water is addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution isfilled in suitable containers.

Example 43 Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate arevigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, comprising each 20mg of the active ingredient.

Example 44 Film-Coated Tablets Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90®) in about 200 mlof water. The wet powder mixture is sieved, dried and sieved again. Thenthere are added 100 g microcrystalline cellulose (Avicel®) and 15 ghydrogenated vegetable oil (Sterotex®). The whole is mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 g methyl cellulose (Methocel 60 HG®) in 75 ml ofdenaturated ethanol there is added a solution of 5 g of ethyl cellulose(Ethocel 22 cps®) in 150 ml of dichloromethane. Then there are added 75ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g ofpolyethylene glycol is molten and dissolved in 75 ml of dichloromethane.The latter solution is added to the former and then there are added 2.5g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml ofconcentrated colour suspension (Opaspray K-1-2109®) and the whole ishomogenated. The tablet cores are coated with the thus obtained mixturein a coating apparatus.

Example 45 Injectable Solution

1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate aredissolved in about 0.51 of boiling water for injection. After cooling toabout 50° C. there are added while stirring 4 g lactic acid, 0.05 gpropylene glycol and 4 g of the A.I. The solution is cooled to roomtemperature and supplemented with water for injection q.s. ad 1 l,giving a solution comprising 4 mg/ml of A.I. The solution is sterilizeby filtration (U.S.P. XVII p. 811) and filled in sterile containers.

What is claimed is:
 1. A compound having the formula:

wherein: R^(1H) represents hydrogen; R² represents hydrogen or methyl;R³ represents hydrogen or C₁₋₆alkyl; R⁴ and R⁵ each independentlyrepresent hydrogen, C₁₋₆alkyl, halo, cyano, nitro, trifluoromethyl,hydroxy, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino orC₁₋₆alkylcarbonylamino; R⁶ represents hydrogen or methyl; and R⁷represents hydrogen or methyl.
 2. A compound as defined by claim 1wherein R⁴ and R⁵ each independently are hydrogen, C₁₋₆alkyl, halo,cyano, nitro, trifluoromethyl, hydroxy, C₁₋₆alkyloxy, amino or mono- ordi(C₁₋₆alkyl)amino; and R⁶ and R⁷ are hydrogen.
 3. A compound accordingto claim 1 wherein R⁴ and R⁵ each independently are hydrogen, C₁₋₆alkyl,halo, cyano, nitro, trifluoromethyl, hydroxy, C₁₋₆alkyloxy, amino ormono- or di(C₁₋₆alkyl)amino; and R⁶ is methyl, R⁷ is hydrogen.
 4. Acompound according to claim 1 wherein R⁴ and R⁵ each independently arehydrogen, C₁₋₆alkyl, halo, cyano, nitro, amino, trifluoromethyl, hydroxyor C₁₋₆alkyloxy.
 5. A compound according to claim 3 wherein R² and R³each independently are hydrogen or methyl.
 6. A compound according toclaim 4 wherein R⁵ and R⁷ are hydrogen.
 7. A compound according to claim6 wherein R⁶ is hydrogen.
 8. A compound according to claim 7 wherein R⁴is hydrogen, methyl, chloro or bromo.